Search

A comprehensive understanding of the intricate cellular and molecular changes governing the complex interactions between cells within acne lesions is currently lacking. Herein, we analyzed early papules from six subjects with active acne vulgaris, utilizing single-cell and high-resolution spatial RNA sequencing. We observed significant changes in signaling pathways across seven different cell types when comparing lesional skin samples (LSS) to healthy skin samples (HSS). Using CellChat, we constructed an atlas of signaling pathways for the HSS, identifying key signal distributions and cell-specific genes within individual clusters. Further, our comparative analysis revealed changes in 49 signaling pathways across all cell clusters in the LSS- 4 exhibited decreased activity, whereas 45 were upregulated, suggesting that acne significantly alters cellular dynamics. We identified ten molecules, including GRN, IL-13RA1 and SDC1 that were consistently altered in all donors. Subsequently, we focused on the function of GRN and IL-13RA1 in TREM2 macrophages and keratinocytes as these cells participate in inflammation and hyperkeratinization in the early stages of acne development. We evaluated their function in TREM2 macrophages and the HaCaT cell line. We found that GRN increased the expression of proinflammatory cytokines and chemokines, including IL-18, CCL5, and CXCL2 in TREM2 macrophages. Additionally, the activation of IL-13RA1 by IL-13 in HaCaT cells promoted the dysregulation of genes associated with hyperkeratinization, including KRT17, KRT16, and FLG. These findings suggest that modulating the GRN-SORT1 and IL-13-IL-13RA1 signaling pathways could be a promising approach for developing new acne treatments.

Different convergent evolutionary strategies adopted by angiosperm fruits lead to diverse functional seed dispersal units. Dry dehiscent fruits are a common type of fruit, characterized by their lack of fleshy pericarp and the release of seeds at maturity through openings (dehiscence zones, DZs) in their structure. In previous decades, a set of core players in DZ formation have been intensively characterized in Arabidopsis and integrated in a gene regulatory network (GRN) that explains the morphogenesis of these tissues. In this work, we compile all the experimental data available to date to build a discrete Boolean model as a mechanistic approach to validate the network and, if needed, to identify missing components of the GRN and/or propose new hypothetical regulatory interactions, but also to provide a new formal framework to feed further work in Brassicaceae fruit development and the evolution of seed dispersal mechanisms. Hence, by means of exhaustive in-silico validations and experimental evidence, we are able to incorporate both the NO TRANSMITTING TRACT (NTT) transcription factor as a new additional node, and a new set of regulatory hypothetical rules to uncover the dynamics of Arabidopsis DZ specification. [ABSTRACT FROM AUTHOR]

IntroductionOne goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.MethodsLEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.ResultsPreviously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DiscussionResults suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.HighlightsSequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

Critical reprogramming factors resided predominantly in the oocyte or male pronucleus can enhance the efficiency or the quality of induced pluripotent stem cells (iPSCs) induction. However, few reprogramming factors exist in the male pronucleus had been verified. Here, we demonstrated that granulin (Grn), a factor enriched specifically in male pronucleus, can significantly improve the generation of iPSCs from mouse fibroblasts. Grn is highly expressed on Day 1, Day 3, Day 14 of reprogramming induced by four Yamanaka factors and functions at the initial stage of reprogramming. Transcriptome analysis indicates that Grn can promote the expression of lysosome‐related genes, while inhibit the expression of genes involved in DNA replication and cell cycle at the early reprogramming stage. Further verification determined that Grn suppressed cell proliferation due to the arrest of cell cycle at G2/M phase. Moreover, ectopic Grn can enhance the lysosomes abundance and rescue the efficiency reduction of reprogramming resulted from lysosomal protease inhibition. Taken together, we conclude that Grn serves as an activator for somatic cell reprogramming through mitigating cell hyperproliferation and promoting the function of lysosomes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin‐3 (Gal‐3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal‐3 levels in patients with FTD and assess its diagnostic potential. METHODS: We examined Gal‐3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal‐3 levels and other FTD markers were explored. RESULTS: Gal‐3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal‐3 levels were higher in cases with tau pathology than TAR‐DNA Binding Protein 43 (TDP‐43) pathology. Only MAPT mutation carriers displayed increased Gal‐3 levels in CSF samples, which correlated with total tau and 14‐3‐3. DISCUSSION: Our findings underscore the potential of Gal‐3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal‐3 with neuronal injury markers. [ABSTRACT FROM AUTHOR]

Chunhui Jiang,1– 3 Jiani Chen,1– 3 Tong Sun,2,3 Jiaqin Xu,2,3 Hongguo Zhu,2,3 Jiaxi Chen1– 3 1School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, People’s Republic of China; 2Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China; 3Department of Laboratory Medicine, Enze Hospital, Taizhou Enze Medical Center (Group), Taizhou, People’s Republic of ChinaCorrespondence: Jiaxi Chen, Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen Street, Linhai, Zhejiang Province, 317000, People’s Republic of China, Tel +86-13606652901, Email chenjx@enzemed.comPurpose: The pathogenesis of T cell subsets in sepsis during the body’s resistance to infection is currently unknown. We aimed to investigate the dynamics and molecular mechanisms of T cells during the development of sepsis.Patients and Methods: Perform single-cell data analysis on peripheral blood mononuclear cells (PBMCs) specimen samples from seven healthy controls, five early-stage sepsis patients, and four late sepsis patients, and the atlas were mapped and analyzed using reference mapping to identify the T cell subpopulations specific to early sepsis. Expression network upstream to investigate the changes of regulatory transcription factors and pathways by pySCENIC.Results: Twenty-two CD4+ T-cell subpopulations and 10 CD8+ T-cell subpopulations were identified by mapping analysis. At the early stage of sepsis, we observed altered ratios of multiple immune cells in PBMCs. Three cell types CD4 Tn cells, CD8 (GZMK+ early Tem), and CD8 (ZNF683+CXCR6− Tm) showed an upward trend (p < 0.05) in the early stages of sepsis compared to normal and returned to normal levels after two weeks. In addition, we found the presence of four sepsis-specific transcription factors (MXI1, CHD1, ARID5A, KLF9) in these three types of cells, which were validated in two external datasets. The differentially expressed genes in CD4 Tn cells, CD8 (GZMK+ early Tem), and CD8 (ZNF683+CXCR6− Tm) cells between the healthy group and the early-stage sepsis group are commonly enriched in the allograft rejection pathway. In addition, it was found that CD8 cells exhibit a trend towards differentiation into CD8 Temra cells in sepsis.Conclusion: We successfully depicted the dynamic changes of T cell subsets during sepsis onset and progression, which provides important clues for an in-depth understanding of T cells’ function and regulatory mechanisms during sepsis pathogenesis.Keywords: scRNA-seq, pySCENIC, GRN, reference mapping

Different convergent evolutionary strategies adopted by angiosperm fruits lead to diverse functional seed dispersal units. Dry dehiscent fruits are a common type of fruit, characterized by their lack of fleshy pericarp and the release of seeds at maturity through openings (dehiscence zones, DZs) in their structure. In previous decades, a set of core players in DZ formation have been intensively characterized in Arabidopsis and integrated in a gene regulatory network (GRN) that explains the morphogenesis of these tissues. In this work, we compile all the experimental data available to date to build a discrete Boolean model as a mechanistic approach to validate the network and, if needed, to identify missing components of the GRN and/or propose new hypothetical regulatory interactions, but also to provide a new formal framework to feed further work in Brassicaceae fruit development and the evolution of seed dispersal mechanisms. Hence, by means of exhaustive in-silico validations and experimental evidence, we are able to incorporate both the NO TRANSMITTING TRACT (NTT) transcription factor as a new additional node, and a new set of regulatory hypothetical rules to uncover the dynamics of Arabidopsis DZ specification.

Endothelial and erythropoietic lineages arise from a common developmental progenitor. Etv2 is a master transcriptional regulator required for the development of both lineages. However, the mechanisms through which Etv2 initiates the gene-regulatory networks (GRNs) for endothelial and erythropoietic specification and how the two GRNs diverge downstream of Etv2 remain incompletely understood. Here, by analyzing a hypomorphic Etv2 mutant, we demonstrate different threshold requirements for initiation of the downstream GRNs for endothelial and erythropoietic development. We show that Etv2 functions directly in a coherent feedforward transcriptional network for vascular endothelial development, and a low level of Etv2 expression is sufficient to induce and sustain the endothelial GRN. In contrast, Etv2 induces the erythropoietic GRN indirectly via activation of Tal1, which requires a significantly higher threshold of Etv2 to initiate and sustain erythropoietic development. These results provide important mechanistic insight into the divergence of the endothelial and erythropoietic lineages.

Abstract Background Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.

Background: Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer 's disease (AD) patients. Objective: Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2, and APP). In addition, Microtubule-associated protein tau (MAPT) gene was studied too. All patients underwent an extensive neuropsychological battery. Methods: Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records. Results: Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect. Conclusions: Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process. [ABSTRACT FROM AUTHOR]

In this manuscript, we introduced a French EOAD patient in Korea who carried the presenilin-1 (PSEN1) Glu318Gly mutations with four possible risk variants, including sortilin-related receptor 1 (SORL1) Glu270Lys, ATP-binding cassette subfamily A member 7 (ABCA7) Val1946Met, translocase of outer mitochondrial membrane 40 (TOMM40) Arg239Trp, and granulin (GRN) Ala505Gly. The patient started to present memory decline and behavioral dysfunction in his early 60s. His brain imaging presented amyloid deposits by positron emission tomography (PET-CT). The multimer detection system (MDS) screening test for plasma for amyloid oligomers was also positive, which supported the AD diagnosis. It was verified that PSEN1 Glu318Gly itself may not impact amyloid production. However, additional variants were found in other AD and non-AD risk genes, as follows: SORL1 Glu270Lys was suggested as a risk mutation for AD and could increase amyloid peptide production and impair endosome functions. ABCA7 Val1946Met was a novel variant that was predicted to be damaging. The GRN Ala505Gly was a variant with uncertain significance; however, it may reduce the granulin levels in the plasma of dementia patients. Pathway analysis revealed that PSEN1 Glu318Gly may work as a risk factor along with the SORL1 and ABCA7 variants since pathway analysis revealed that PSEN1 could directly interact with them through amyloid-related and lipid metabolism pathways. TOMM40 and PSEN1 could have common mechanisms through mitochondrial dysfunction. It may be possible that PSEN1 Glu318Gly and GRN Ala505Gly would impact disease by impairing immune-related pathways, including microglia and astrocyte development, or NFkB-related pathways. Taken together, the five risk factors may contribute to disease-related pathways, including amyloid and lipid metabolism, or impair immune mechanisms. [ABSTRACT FROM AUTHOR]

Gene regulatory networks (GRNs) reveal the complex molecular interactions that govern cell state. However, it is challenging for identifying causal relations among genes due to noisy data and molecular nonlinearity. Here, we propose a novel causal criterion, neighbor cross-mapping entropy (NME), for inferring GRNs from both steady data and time-series data. NME is designed to quantify 'continuous causality' or functional dependency from one variable to another based on their function continuity with varying neighbor sizes. NME shows superior performance on benchmark datasets, comparing with existing methods. By applying to scRNA-seq datasets, NME not only reliably inferred GRNs for cell types but also identified cell states. Based on the inferred GRNs and further their activity matrices, NME showed better performance in single-cell clustering and downstream analyses. In summary, based on continuous causality, NME provides a powerful tool in inferring causal regulations of GRNs between genes from scRNA-seq data, which is further exploited to identify novel cell types/states and predict cell type-specific network modules. [ABSTRACT FROM AUTHOR]

BackgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.MethodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X-/- KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X.ResultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X-/- KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X-/- KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X-/- KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice.ConclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

GRN mutations, causing frontotemporal dementia, can be associated with atypical white matter hyperintensities (WMH). We hypothesized that the presence of WMH may impact neurofilament light chain (NfL) levels, markers of neuroaxonal damage. We analyzed plasma NfL in 20 GRN patients and studied their association to visually-scored WMH burden. The 12 patients displaying atypical WMH had significantly higher NfL levels (98.4±34.9 pg/mL) than those without WMH (47.2±29.4 pg/mL, p = 0.003), independently from age, disease duration and Fazekas-Schmidt grade. NfL correlated with WMH burden (rho = 0.55, p = 0.01). This study prompts considering WMH burden as a variability factor when evaluating NfL levels in GRN patients. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and gradual joint degeneration, resulting in function disability. Recently, ferroptosis, a novel form of regulated cell death that involves iron-dependent lipid peroxidation, has been implicated in the pathogenesis of RA. However, the underlying molecular mechanisms and key genes involved in ferroptosis in RA remain largely unknown. Methods: The GSE134420 and GSE77298 datasets were downloaded and DEGs were identified using R software. The DEGs were then mapped to the dataset of 619 ferroptosis-related genes obtained from the GeneCards database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to investigate the possible biological functions. Protein-protein interaction (PPI) networks were constructed to identify the hub genes. The relationship between hub genes and immune infiltration was estimated using the CIBERSORT algorithms. Gene Set Enrichment Analysis (GSEA) was used to explore the underlying signaling pathways of hub genes. Genome-wide association studies (GWAS) analysis was performed to confirm the pathogenic regions of the hub genes. RcisTarget and Gene-motif ranking databases were used to identify transcription factors (TFs) associated with the hub genes. The miRcode databases were utilized to construct the microRNA (miRNA)-messenger RNA (mRNA) network. Single-cell analysis was utilized to cluster cells and display the expression of hub genes in cell clusters. Finally, the expression and potential mechanism of hub genes were investigated in human and experimental samples. Results: Three hub genes PTGS2, ENO1, and GRN highly associated with ferroptosis were identified. Four pathogenic genes HLA-B, MIF, PSTPIP, TLR1 were identified that were significantly and positively correlated with the expression levels of hub genes. The results of the GSEA showed that the hub genes were significantly enriched in pathways related to immunity, lysosome, phagocytosis and infection. ENO1 and PTGS2 were enriched in the TF-binding motif of cisbp_M5493. The hub genes were validated in experimental and patient samples and highly level of ENO1 expression was found to inhibit ACO1, which reduces ferroptosis in proliferating fibroblast-like synoviocytes (FLS). [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is a complex neurodegenerative disorder, characterized by a wide range of pathological conditions associated with the buildup of proteins such as tau and TDP-43. With a strong hereditary component, FTD often results from genetic variants in three genes - MAPT, GRN, and C9orf72. In this review, the authors explore abnormal protein accumulation in FTD and forthcoming treatments, providing a detailed analysis of new diagnostic advancements, including innovative markers. They analyze how these discoveries have influenced therapeutic strategies, particularly disease-modifying treatments, which could potentially transform FTD management. This comprehensive exploration of FTD from its molecular underpinnings to its therapeutic prospects offers a compelling overview of the current state of FTD research. Notable challenges in FTD management involve identifying reliable biomarkers for early diagnosis and response monitoring. Genetic forms of FTD, particularly those linked to C9orf72 and GRN, show promise, with targeted therapies resulting in substantial progress in disease-modifying strategies. The potential of neuromodulation techniques, like tDCS and rTMS, is being explored, requiring further study. Ongoing trials and multi-disciplinary care highlight the continued push toward effective FTD treatments. With increasing understanding of FTD's molecular and clinical intricacies, the hope for developing effective interventions grows. [ABSTRACT FROM AUTHOR]

ObjectiveThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other.MethodsIndividuals were classified using the Clinical Dementia Rating (CDR® ) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated.ResultsThe cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = -0.20, P = .001), as were ZBI and DEMQOL (r = -0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

IntroductionFrontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.MethodsIn March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.ResultsChallenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges.DiscussionNew personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.

IntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

IntroductionFamilial frontotemporal lobar degeneration (f-FTLD) due to autosomal dominant mutations is an important entity for developing treatments for FTLD. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) longitudinal studies were designed to describe the natural history of f-FTLD.MethodsWe summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f-FTLD.ResultsPublished and emerging studies are producing data on all phases of f-FTLD, including the asymptomatic and symptomatic phases of disease, as well as the transitional phase when symptoms are just beginning to develop. These data indicate that rates of change increase along with disease severity, which is consistent with commonly cited models of neurodegeneration, and that measurement of biomarkers may predict onset of symptoms.DiscussionData from large multisite studies are producing important data on the natural history of f-FTLD that will be critical for planning intervention trials.

IntroductionIt is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase.MethodsThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72.ResultsWe present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol.DiscussionThese data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

IntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Abstract Background Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 repeat expansion and FTD-MND-related TDP-43 neuropathology for future diagnostics and intervention studies.

Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD. [ABSTRACT FROM AUTHOR]

While frontotemporal dementia (frontotemporal dementia) has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with aging. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we have examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between the ages of 19 and 30y. Structural brain differences and improved performance on some cognitive tests was found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26y. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia causing genetic mutations. These results have implications for design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes in the neurodevelopmental period. [ABSTRACT FROM AUTHOR]

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer's disease, characterized by distinct changes in behavior, personality, and language. Our study performed whole exome sequencing and repeat-primed PCR analysis in 29 unrelated FTD patients. Consequently, 2 known pathogenic variants (MAPT : p.P301L; TBK1 : p.I450Kfs), and 4 novel variants (MAPT : p.R406Q, p.D430H, p.A330D; GRN : c.350-2A>G) were identified. The functional analysis results showed that phosphorylated tau levels were higher in cells expressing p.R406Q and p.D430H tau than those expressing wild-type tau, especially at the Thr205, Thr231, and Ser396 phosphorylation epitopes. Besides, the p.R406Q and p.D430H variants of MAPT impaired the ability of tau to bind to the microtubules and increased tau self-aggregation. Furthermore, we found that the c.350-2A>G variant caused exon 5 skipping. Our results showed that p.R406Q, p.D430H, and c.350-2A>G variants were classified as pathogenic. Finally, we summarized the clinical characterization of patients carrying pathogenic variants of MAPT in the East Asia populations. Our results broaden the genetic spectrum of FTD with MAPT and GRN variants. [ABSTRACT FROM AUTHOR]

Innovations in metazoan development arise from evolutionary modification of gene regulatory networks (GRNs). We report widespread cryptic variation in the requirement for two key regulatory inputs, SKN-1/Nrf2 and MOM-2/Wnt, into the C. elegans endoderm GRN. While some natural isolates show a nearly absolute requirement for these two regulators, in others, most embryos differentiate endoderm in their absence. GWAS and analysis of recombinant inbred lines reveal multiple genetic regions underlying this broad phenotypic variation. We observe a reciprocal trend, in which genomic variants, or knockdown of endoderm regulatory genes, that result in a high SKN-1 requirement often show low MOM-2/Wnt requirement and vice-versa, suggesting that cryptic variation in the endoderm GRN may be tuned by opposing requirements for these two key regulatory inputs. These findings reveal that while the downstream components in the endoderm GRN are common across metazoan phylogeny, initiating regulatory inputs are remarkably plastic even within a single species.

IntroductionPrimary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease.MethodsWe screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases.ResultsIn this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP mutation. Rare risk variants, TREM2 R47H and MAPT A152T, were associated with a three- to seven-fold increase in risk for PPA.DiscussionOur results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43- than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.

This research aims to implement Public Protection and Disaster Relief (PPDR) planning using Terrestrial Trunked Radio (TETRA) in the West Java area. This plan will work at frequencies 806-821 MHz and 851-866 MHz (bandwidth of 15 MHz). PPDR planning study using TETRA in West Java with a total area of 37,315 Km2. This TETRA planning study uses the simulation method. Simulation using ATOLL software using parameters used by the West Java Regional Police (Polda) because it follows the conditions of the province of West Java. This plan does three things, firstly plans the coverage area to determine the number of base stations by looking for the link power budget and MAPL, followed by finding the cell radius value, secondly planning the network capacity to be used by following the assumptions and predictions of the TETRA mobile station (ms), and the third is planning the frequency spectrum. The three methods are tested and validated using Atoll software simulation. The planning results for the West Java region required 58 sites (base station). The required channels are 94 channels, while from 15 MHz, TETRA digital radio trunking bandwidth provides 600 channels so that TETRA digital trunking radio can be implemented in West Java. In the future, this TETRA radio trunking plan can be implemented in other provinces in Indonesia and even be expanded to all regions in Indonesia to handle disasters

Abstract Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer’s disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.

BackgroundAmong primary brain tumors, gliomas are associated with a poor prognosis and a median survival that varies depending on the tumor grade and subtype. As the most malignant form of glioma, glioblastoma (GBM) constitutes a significant health concern. Alteration in granulin(GRN) has been proved to be accountable for several diseases. However, the relationship between GRN and GBM remains unclear. We evaluated the role of GRN in GBM through The Cancer Genome Atlas (TCGA) databaseMethodsFirst, we assessed the relationship between GRN and GBM through the GEPIA database. Next, the relationship between GRN and GBM prognosis was analyzed by logistic regression and multivariate cox methods. Using CIBERSORT and the GEPIA correlation module, we also investigated the link between GRN and immune infiltrates in cancer. Using the TCGA data, a gene set enrichment analysis (GSEA) was performed. We also employed Tumor Immune Estimation Resource (TIMER) to examine the data set of GRN expression and immune infiltration level in GBM and investigate the cumulative survival in GBM. We also validated tissues from GBM patients by Western blotting, RT-qPCR, and immunohistochemistry.ResultsIncreased GRN expression was shown to have a significant relationship to tumor grade in a univariate study utilizing logistic regression. Furthermore, multivariate analysis disclosed that GRN expression down-regulation is an independent predictive factor for a favorable outcome. GRN expression level positively correlates with the number of CD4+ T cells, neutrophils, macrophages, and dendritic cells (DCs) that infiltrate a GBM. The GSEA also found that the high GRN expression phenotype pathway was enriched for genes involved in immune response molecular mediator production, lymphocyte-mediated immunity, cytokine-mediated signaling pathway, leukocyte proliferation, cell chemotaxis, and CD4+ alpha beta T cell activation. Differentially enriched pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) include lysosome, apoptosis, primary immunodeficiency, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and B cell receptor signaling pathway. Validated result showed that GRN was upregulated in GBM tissues. These results suggested that GRN was a potential indicator for the status of GBM.ConclusionGRN is a prognostic biomarker and correlated with immune infiltrates in GBM.

Frontotemporal Dementia (FTD) represents a highly heritable neurodegenerative disorder. Most of the heritability is caused by autosomal dominant mutations in the Microtubule-Associated Protein Tau (MAPT), Progranulin (GRN), and the pathologic exanucleotide expansion of C9ORF72 genes. At the pathological level, either the tau or the TAR DNA-binding protein (TDP-43) account for almost all cases of FTD. Pathogenic mechanisms are just arising, and the emerging role of non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long non-coding RNAs (lncRNAs), have become increasingly evident. Using specific arrays, an exploratory analysis testing the expression levels of 84 miRNAs and 84 lncRNAs has been performed in a population consisting of 24 genetic FTD patients (eight GRN, eight C9ORF72, and eight MAPT mutation carriers), eight sporadic FTD patients, and eight healthy controls. The results showed a generalized ncRNA downregulation in patients carrying GRN and C9ORF72 when compared with the controls, with statistically significant results for the following miRNAs: miR-155-5p (Fold Change FC: 0.45, p = 0.037 FDR = 0.52), miR-15a-5p (FC: 0.13, p = 0.027, FDR = 1), miR-222-3p (FC: 0.13, p = 0.027, FDR = 0.778), miR-140-3p (FC: 0.096, p = 0.034, FRD = 0.593), miR-106b-5p (FC: 0.13, p = 0.02, FDR = 0.584) and an upregulation solely for miR-124-3p (FC: 2.1, p = 0.01, FDR = 0.893). Conversely, MAPT mutation carriers showed a generalized robust upregulation in several ncRNAs, specifically for miR-222-3p (FC: 22.3, p = 7 × 10−6, FDR = 0.117), miR-15a-5p (FC: 30.2, p = 0.008, FDR = 0.145), miR-27a-3p (FC: 27.8, p = 6 × 10−6, FDR = 0.0005), miR-223-3p (FC: 18.9, p = 0.005, FDR = 0.117), and miR-16-5p (FC: 10.9, p = 5.26 × 10−5, FDR = 0.001). These results suggest a clear, distinctive pattern of dysregulation among ncRNAs and specific enrichment gene pathways between mutations associated with the TDP-43 and tau pathologies. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort. [ABSTRACT FROM AUTHOR]

[Display omitted] • GRN is significantly more highly expressed in PSA. • GRN knockdown is associated with changes in transcription levels and the occurrence of alternative splicing events. • GRN is involved in a variety of biological processes. Prior research has shown that granulin precursor (GRN, also termed PGRN) is closely linked to aphasia. However, there has been little research on the mechanism of action of GRN in post-stroke aphasia (PSA). In this study, RT-qPCR was used to identify variations in gene expression, while RNA sequencing (RNA-seq) was utilized to acquire transcriptional profiles. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were employed for bioinformatics analysis. GRN was considerably more active in PSA subjects. After silencing the GRN, 197 transcripts had differential expression, and 237 alternative splicing events (ASEs) were substantially affected. The analysis of differentially expressed genes (DEGs) using GO and KEGG approaches showed that these genes have various molecular functions and are significantly enriched in metabolic signaling pathways. Regarding Alternative Splicing (AS), the GO and KEGG analyses revealed numerous functional genes involved in transcription and metabolism. The knockdown of GRN has been shown to be associated with alterations in transcription, metabolism, and ASEs, potentially impacting transcriptional and metabolic pathways through its involvement in AS. Furthermore, GRN knockdown is associated with nervous system disease-related gene transcription and AS processes, as well as its involvement in G protein-coupled receptor (GPCR) and wingless/integrated (Wnt) signaling pathways, which impact the initiation and resolution of PSA. [ABSTRACT FROM AUTHOR]

C4 photosynthesis evolved from ancestral C3 photosynthesis by recruiting pre-existing genes to fulfill new functions. The enzymes and transporters required for the C4 metabolic pathway have been intensively studied and well documented; however, the transcription factors (TFs) that regulate these C4 metabolic genes are not yet well understood. In particular, how the TF regulatory network of C4 metabolic genes was rewired during the evolutionary process is unclear. Here, we constructed gene regulatory networks (GRNs) for four closely evolutionarily related species from the genus Flaveria, which represent four different evolutionary stages of C4 photosynthesis: C3 (F. robusta), type I C3-C4 (F. sonorensis), type II C3-C4 (F. ramosissima), and C4 (F. trinervia). Our results show that more than half of the co-regulatory relationships between TFs and core C4 metabolic genes are species specific. The counterparts of the C4 genes in C3 species were already co-regulated with photosynthesis-related genes, whereas the required TFs for C4 photosynthesis were recruited later. The TFs involved in C4 photosynthesis were widely recruited in the type I C3-C4 species; nevertheless, type II C3-C4 species showed a divergent GRN from C4 species. In line with these findings, a 13CO2 pulse-labeling experiment showed that the CO2 initially fixed into C4 acid was not directly released to the Calvin–Benson–Bassham cycle in the type II C3-C4 species. Therefore, our study uncovered dynamic changes in C4 genes and TF co-regulation during the evolutionary process; furthermore, we showed that the metabolic pathway of the type II C3-C4 species F. ramosissima represents an alternative evolutionary solution to the ammonia imbalance in C3-C4 intermediate species.

Frontotemporal lobar degeneration (FTLD) is a complex disease, characterized by progressive degeneration of frontal and temporal lobes. Mutations in progranulin (GRN) gene have been found in up to 50% of patients with familial FTLD. Abnormal deposits of post-translationally-modified TAR DNA-binding protein of 43 kDa (TDP-43) represent one of the main hallmarks of the brain pathology. To investigate in peripheral cells the presence of the different TDP-43 forms, especially the toxic 25 kDa fragments, we analyzed lymphoblastoid cell lines (LCLs) and the derived extracellular vesicles (EVs) from patients carrying a GRN mutation, together with wild-type (WT) healthy controls. After characterizing EV sizes and concentrations by nanoparticle tracking analysis, we investigated the levels of different forms of the TDP-43 protein in LCLs and respective EVs by Western blot. Our results showed a trend of concentration decreasing in EVs derived from GRN-mutated LCLs, although not reaching statistical significance. A general increase in p-TDP-43 levels in GRN-mutated LCLs and EVs was observed. In particular, the toxic 25 kDa fragments of p-TDP-43 were only present in GRN-mutated LCLs and were absent in the WT controls. Furthermore, these fragments appeared to be more concentrated in EVs than in LCLs, suggesting a relevant role of EVs in spreading pathological molecules between cells. [ABSTRACT FROM AUTHOR]

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10–12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (−5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods: The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results: Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions: Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 repeat expansion and FTD-MND-related TDP-43 neuropathology for future diagnostics and intervention studies. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) biomarkers, namely total tau, phospho-tau and amyloid beta peptides, have received much attention specifically regarding Alzheimer's disease (AD), since they can detect the biochemical fingerprint of AD and serve as a diagnostic tool for accurate and early diagnosis during life. In the same way, biomarkers for other neurodegenerative disease pathologies are also needed. We present a case series of six patients with genetic frontotemporal dementia (FTD), with TDP-43 underlying proteinopathy, in an attempt to assess TDP-43 as a novel biomarker alone and in combination with established AD biomarkers for this specific patient group, based on the principles of personalized and precision medicine. Our results indicate that genetic TDP-43-FTD is characterized by increased CSF TPD-43 and increased TDP-43 × τΤ/τP-181 combination. Hence, TDP-43 combined with tau proteins could be a useful tool for the diagnosis of genetic FTD with TDP-43 underling histopathology, supplementing clinical, neuropsychological and imaging data. [ABSTRACT FROM AUTHOR]

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD. [ABSTRACT FROM AUTHOR]

Purpose: Ceroid lipofuscinosis type 11 (CLN11) is a very rare disease, being reported in only 13 unrelated families so far. Further reports are necessary to comprehend the clinical phenotype of this condition. This article aims to report 9 additional cases of CLN11 from 9 unrelated Latin American families presenting with relatively slow disease progression., Methods: This was a retrospective observational study including patients with CLN11. Patients were identified through an active search for granulin precursor gene (GRN) pathogenic variants across the entire database of next-generation sequencing of a commercial laboratory and by contacting attending physicians to check for clinical and radiologic findings compatible with a neuronal ceroid lipofuscinosis phenotype., Results: Nine CLN11 patients from unrelated families were evaluated. Age of onset varied between 3 to 17 years. The most common findings were visual impairment, cerebellar ataxia, seizures, myoclonus, and cognitive decline. One patient had a previously unreported finding of cervical, perioral, and tongue myoclonus. Most of the patients were able to walk unassisted after an average of 14.2 years (SD 4.76 y) from disease onset., Conclusion: We describe 9 new cases of a very rare type of neuronal ceroid lipofuscinosis (CLN11) from Latin America with a recurrent p.(Gln257ProfsTer27) and a novel p.(Cys83Ter) nonsense variant. Our findings suggest that a slowly progressive neuronal ceroid lipofuscinosis might be a clue for the diagnosis of CLN11., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Familial frontotemporal lobar degeneration (FTLD) is a pathologically heterogeneous group of neurodegenerative diseases with diverse genotypes and clinical phenotypes. Three major mutations were reported in patients with familial FTLD, namely, progranulin (GRN), microtubule-associated protein tau (MAPT), and the chromosome 9 open reading frame 72 (C9orf72) repeat expansion, which could cause neurodegenerative pathological changes years before symptom onset. Noninvasive quantitative molecular imaging with PET or single-photon emission CT (SPECT) allows for selective visualization of the molecular targets in vivo to investigate brain metabolism, perfusion, neuroinflammation, and pathophysiological changes. There was increasing evidence that several molecular imaging biomarkers tend to serve as biomarkers to reveal the early brain abnormalities in familial FTLD. Tau-PET with 18F-flortaucipir and 11C-PBB3 demonstrated the elevated tau position in patients with FTLD and also showed the ability to differentiate patterns among the different subtypes of the mutations in familial FTLD. Furthermore, dopamine transporter imaging with the 11C-DOPA and 11C-CFT in PET and the 123I-FP-CIT in SPECT revealed the loss of dopaminergic neurons in the asymptomatic and symptomatic patients of familial FTLD. In addition, PET imaging with the 11C-MP4A has demonstrated reduced acetylcholinesterase (AChE) activity in patients with FTLD, while PET with the 11C-DAA1106 and 11C-PK11195 revealed an increased level of microglial activation associated with neuroinflammation even before the onset of symptoms in familial FTLD. 18F-fluorodeoxyglucose (FDG)-PET indicated hypometabolism in FTLD with different mutations preceded the atrophy on MRI. Identifying molecular imaging biomarkers for familial FTLD is important for the in-vivo assessment of underlying pathophysiological changes with disease progression and future disease-modifying therapy. We review the recent progress of molecular imaging in familial FTLD with focused on the possible implication of these techniques and their prospects in specific mutation types. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia- GRN (FTD- GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action. Progranulin (PGRN) is a secreted, immune regulatory protein produced by myeloid cells and some neurons that regulates lysosomal function, neuronal survival, and inflammation. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis and frontotemporal dementia- GRN (FTD- GRN) in a dosage-dependent manner. Mutations that reduce PGRN levels are also associated with higher risk for amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene, Parkinson's disease (PD), Alzheimer's disease (AD), limbic-predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, Gaucher disease, and autism. PGRN overexpression is protective in animal models for AD, PD, FTD, ALS, stroke, Gaucher disease, and arthritis. PGRN is being investigated as a therapeutic target for neurodegenerative diseases through multiple mechanisms of action. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer's disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies. [ABSTRACT FROM AUTHOR]