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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]

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]

Introduction: One 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. Methods: LEADS 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. Results: Previously 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. Discussion: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. Highlights: Sequencing 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 [ABSTRACT FROM AUTHOR]

Introduction: The possibility to generalize our understandings on treatments and assessments to both familial frontotemporal dementia (f-FTD) and sporadic FTD (s-FTD) is a fundamental perspective for the near future, considering the constant advancement in potential disease-modifying therapies that target particular genetic forms of FTD. We aimed to investigate differences in clinical features, cerebrospinal fluid (CSF), and blood-based biomarkers between f-FTD and s-FTD. Methods: In this longitudinal cohort study, we evaluated a consecutive sample of symptomatic FTD patients, classified as f-FTD and s-FTD according to Goldman scores (GS). All patients underwent clinical, behavioral, and neuropsychiatric symptom assessment, CSF biomarkers and serum neurofilament light (NfL) analysis, and brain atrophy evaluation with magnetic resonance imaging. Results: Of 570 patients with FTD, 123 were classified as f-FTD, and 447 as s-FTD. In the f-FTD group, 95 had a pathogenic FTD mutationwhile 28 were classified as GS = 1 or 2; of the s-FTD group, 133 were classified as GS = 3 and 314 with GS = 4. f-FTD and s-FTD cases showed comparable demographic features, except for younger age at disease onset, age at diagnosis, and higher years of education in the f-FTD group (all P < .05). f-FTD showed worse behavioral disturbances as measured with Frontal Behavioral Inventory (FBI) negative behaviors (14.0 ± 7.6 vs. 11.6 ± 7.4, P = .002), and positive behaviors (20.0 ± 11.0 vs. 17.4 ± 11.8, P = .031). Serum NfL concentrations were higher in patients with f-FTD (70.9 ± 37.9 pg/mL) compared to s-FTD patients (37.3 ± 24.2 pg/mL, P < .001), and f-FTD showed greater brain atrophy in the frontal and temporal regions and basal ganglia. Patients with f-FTD had significantly shorter survival than those with s-FTD (P = .004). Discussion: f-FTD and s-FTD are very similar clinical entities, but with different biological mechanisms, and different rates of progression. The parallel characterization of both f-FTD and s-FTD will improve our understanding of the disease, and aid in designing future clinical trials for both genetic and sporadic forms of FTD. [ABSTRACT FROM AUTHOR]

The interplay between extrinsic signaling and downstream gene networks controls the establishment of cell identity during development and its maintenance in adult life. Advances in next‐generation sequencing and single‐cell technologies have revealed additional layers of complexity in cell identity. Here, we review our current understanding of transcription factor (TF) networks as key determinants of cell identity. We discuss the concept of the core regulatory circuit as a set of TFs and interacting factors that together define the gene expression profile of the cell. We propose the core regulatory circuit as a comprehensive conceptual framework for defining cellular identity and discuss its connections to cell function in different contexts. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions in early embryogenesis, anti‐inflammation, and neurodegeneration. A good model for the functional study of PGRN is the zebrafish with knockdown or knockout of grn, the gene encoding PGRN. Morpholino oligonucleotides (MOs) and zinc finger nucleases have been used to generate zebrafish grn models, yet they have shown inconsistent phenotypes due to either the neurotoxicity of the MOs or possible genetic compensation responses during gene editing. In this study, we generated stable grna (one of the major grn homologues of zebrafish) knockout zebrafish by using CRISPR/Cas9‐mediated genome editing. A grna sgRNA was designed to target the similar repeated sequence shared by exon 13, exon 15, and exon 19 in zebrafish. The F1 generation with the frameshift mutation of + 4 bp (the addition of 4 bp to exon15), which causes a premature termination, was obtained and subjected to morphological and behavioral evaluation. The grna knockout zebrafish showed neurodevelopmental defects, including spinal motor neurons with shorter axons, decreased sensory hair cells, thinning of the outer nuclear layer and thickening of the inner nuclear layer of the retina, decreased expression of rhodopsin in the cone cells, and motor behavior changes. Moreover, the phenotypes of grna knockout zebrafish could be rescued with the Tol2 system carrying the grna gene. The grna knockout zebrafish model generated in this study provides a useful tool to study PGRN function and has potential for high‐throughput drug screening for disease therapy. [ABSTRACT FROM AUTHOR]

Objective: The 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. Methods: Individuals 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. Results: The 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 <.0001). Conclusion: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers. [ABSTRACT FROM AUTHOR]

Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE‐NC + HS risk factors in brain bank collections. To replicate these results in independent population‐representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75‐Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti‐pTDP‐43 (n = 713), and evaluated for LATE‐NC + HS and TDP‐43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE‐NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2(2) = 20.61, P < 0.001) and T‐allele (χ2(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A‐allele (χ2(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE‐NC + HS and non‐LATE‐NC + HS neuropathology cases. Dentate gyrus TDP‐43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE‐NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE‐NC + HS. The association between TMEM106B and LATE‐NC + HS may be independent of dentate TDP‐43 pathology. [ABSTRACT FROM AUTHOR]

Introduction: Behavioral 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. Methods: A 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. Results: Participants 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. Discussion: f‐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 FROM AUTHOR]

Introduction: The 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. Methods: We 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. Results: Asymptomatic 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. Discussion: Imaging changes appear to precede clinical changes in familial‐frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals. [ABSTRACT FROM AUTHOR]

Introduction: Frontotemporal 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. Methods: In 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. Results: Challenges 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. Discussion: New 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. [ABSTRACT FROM AUTHOR]

Introduction: It 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. Methods: The 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. Results: We 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. Discussion: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease‐modifying therapeutic trials in f‐FTLD. [ABSTRACT FROM AUTHOR]

Introduction: The 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. Methods: We screened the major dementia‐associated genes in 302 sporadic and 390 familial (symptomatic or at‐risk) participants enrolled in these studies. Results: Among 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. Discussion: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history. [ABSTRACT FROM AUTHOR]

Introduction: Familial 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. Methods: We summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f‐FTLD. Results: Published 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. Discussion: Data from large multisite studies are producing important data on the natural history of f‐FTLD that will be critical for planning intervention trials. [ABSTRACT FROM AUTHOR]

Introduction: Primary 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. Methods: We screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases. Results: In 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. Discussion: Our 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. [ABSTRACT FROM AUTHOR]

Inferring gene regulatory networks (GRNs) from microarray expression data are an important but challenging issue in systems biology. In this study, the authors propose a Bayesian information criterion (BIC)‐guided sparse regression approach for GRN reconstruction. This approach can adaptively model GRNs by optimising the l1 ‐norm regularisation of sparse regression based on a modified version of BIC. The use of the regularisation strategy ensures the inferred GRNs to be as sparse as natural, while the modified BIC allows incorporating prior knowledge on expression regulation and thus avoids the overestimation of expression regulators as usual. Especially, the proposed method provides a clear interpretation of combinatorial regulations of gene expression by optimally extracting regulation coordination for a given target gene. Experimental results on both simulation data and real‐world microarray data demonstrate the competent performance of discovering regulatory relationships in GRN reconstruction. [ABSTRACT FROM AUTHOR]

This study deals with the problem of delay‐dependent dissipative filtering for genetic regulatory networks (GRNs) with norm‐bounded parameter uncertainties and time‐varying delays. It is assumed that the non‐linear function describing the feedback regulation satisfies the sector‐bounded condition. Improved delay‐dependent stochastic stability and filter design method for stochastic GRNs are obtained by applying the delay fractioning technique, Jensen inequalities and introducing some proper slack matrix variables. The conservatism caused by either model transformation or bounding techniques is reduced. Sufficient conditions of the robust stability and filtering problems are proposed, respectively. The filter, which can guarantee the resulting error system to be asymptotically stable in the mean‐square sense and satisfy a prescribed performance level for all delays no larger than a given upper bound, are constructed. A numerical example is provided to demonstrate effectiveness of the proposed results in this study. [ABSTRACT FROM AUTHOR]

Background and purpose: A single nucleotide polymorphism in the 3′-untranslated region of the progranulin gene ( GRN; 3′UTR+78C>T; rs5848) was reported to alter the risk for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). rs5848 is located within a micro-RNA binding site and affects the expression of GRN. Methods: As FTLD-U patients often present with parkinsonism, we investigated the association of GRN rs5848 and risk of Parkinson’s disease in two Caucasian patient–control series ( n = 1413) from the US and Poland. Results: No association was observed between rs5848 and susceptibility to Parkinson’s disease (individual series and combined analysis). Conclusions: This finding shows that GRN rs5848 does not affect the risk of Parkinson’s disease in the US and Polish populations. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 25-year-old female with history of progressive gait impairment and urinary incontinence. It mentions the development of mood lability and delusional thoughts in female and experience photosensitive seizures by visual aura. It also mentions that autosomal dominant frontotemporal lobar degeneration (FTLD) is due to GRN heterozygous mutations.