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Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons in the cerebral cortex, brain stem and spinal cord. The dysfunction and death of motor neurons lead to the progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately the whole paralysis of body. Despite the identification of several genetic mutations associated with the pathogenesis of ALS, including mutations in chromosome 9 open reading frame 72 leading to the abnormal expansion of GGGGCC repeat sequence, TAR DNA-binding protein 43, fused in sarcoma/translocated in liposarcoma, copper/zinc superoxide dismutase 1 (SOD1) and TANK-binding kinase 1, the exact mechanisms underlying the specific degeneration of motor neurons that causes ALS remain incompletely understood. At present, since the transgenic model expressed SOD1 mutants was established, multiple in vitro models of ALS have been developed for studying the pathology, pathophysiology and pathogenesis of ALS as well as searching the effective neurotherapeutics. This review reviewed the details of present established in vitro models used in studying the pathology, pathophysiology and pathogenesis of ALS. Meanwhile, we also discussed the advantages, disadvantages, cost and availability of each models., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Current studies suggest that the abnormal alteration of brain lipid binding protein (BLBP) might participate in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, the detailed understanding of ALS pathogenesis been yet to be elucidated. Therefore, this research intended to explore the potential effects of BLBP in ALS. The observation and analysis of BLBP-altered features in various anatomical areas and different spinal segments was conducted at the pre-onset, onset, and progression stages of Tg(SOD1*G93A)1Gur (TG) mice and the same periods of age-matched SOD1 wild-type (WT) mice by fluorescence immunohistochemistry and western blotting. BLBP-positive cells were comprehensively distributed in various spinal anatomical areas, especially in both the anterior and posterior horn, around the central canal and in anterior, lateral, and posterior funiculi. Overall, BLBP expression tended to increase from the pre-onset to the onset to the progression stages of the same periods of age-matched WT mice. Furthermore, in TG mice, BLBP expression in the entire spinal cord significantly increased from onset to the progression stage. BLBP was expressed in neurons, astrocytes, and radial glial cells, and at the early and late stages of neural precursor cells (NPCs) and was predominantly distributed outside the cell nucleus. The increase of BLBP-positive cells was closely related to neural cell reduction in TG mice. The distribution and increased expression of BLBP among the cervical, thoracic, and lumbar segments of the spinal cord might participate in the development of ALS and exert potential effects in the pathogenesis of ALS by regulating NPCs.

Serotonin (5-HT) participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), but its effects have not been completely clarified. Therefore, we observed the distribution features and potential effects of 5-HT in the cerebrum of G93A SOD1 transgenic (TG) and wild-type (WT) mice by fluorescence immunohistochemistry, Western blotting, ELISA, as well as motor function measurements. Both 5-HT and tryptophan hydroxylase-2 (TPH2) were mainly present in the limbic systems of the cerebrum, such as the glomerular layer of the olfactory bulb, nucleus accumbens, cingulate, fimbria of the hippocampus, mediodorsal thalamic nucleus, habenular nucleus, ventromedial hypothalamus nucleus, lateral hypothalamus area, dorsal raphe nucleus, and piriform cortex. TPH2 and 5-HT were expressed in cell bodies in the dorsal raphe nucleus and piriform cortex, while in other regions they were distributed as filaments and clump shapes in axons. The TPH2 distribution in the cerebrum of TG was significantly lower than that in WT in preset, onset, and progression stages. TPH2 expression in the fimbria of the hippocampus, mediodorsal thalamic nucleus, habenular nucleus, ventromedial hypothalamus nucleus and lateral hypothalamus area was increased in the onset stage and decreased in the progression stage, gradually decreased in the cingulate with disease progression and significantly decreased in the glomerular layer of the olfactory bulb and nucleus accumbens in the onset stage in TG. The number of mammalian achaete-scute homolog-1 in the subventricular zone (SVZ) in TG was significantly lower than that in WT, which was correlated with the TPH2 distribution. Double immunofluorescence staining showed that TPH2, mammalian achaete-scute homolog-1 and 5-HT were mainly expressed in neurons but rarely expressed in microglia or astrocytes in the piriform cortex. The relative fluorescence density of TPH2 in the cingulate region was negatively correlated with the disease severity. Our findings suggest that 5-HT plays a protective role in ALS, likely by regulating neural stem cells in the subventricular zone that might be involved in neuron development in the piriform cortex., (Copyright © 2022 He et al.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with multiple complex mechanisms involved. Among them, mitochondrial dysfunction plays an important role in ALS. Multiple studies have shown that mitochondria are closely associated with reactive oxygen species production and oxidative stress and exhibit different functional states in different genetic backgrounds. In this review we explored the roles of Ca 2+ , autophagy, mitochondrial quality control in the regulation of mitochondrial homeostasis and their relationship with ALS. In addition, we also summarized and analyzed the roles of protein misfolding and abnormal aggregation in the pathogenesis of ALS. Moreover, we also discussed how epigenetic mechanisms such as DNA methylation and protein post-translational modification affect initiation and progression of ALS. Nevertheless, existing events still cannot fully explain the pathogenesis of ALS at present, more studies are required to explore pathological mechanisms of ALS., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and its candidate biomarkers have not yet been fully elucidated in previous studies. Therefore, with the present study, we aim to define and verify effective biomarkers of ALS by bioinformatics. Here, we employed differentially expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), enrichment analysis, immune infiltration analysis, and protein-protein interaction (PPI) to identify biomarkers of ALS. To validate the biomarkers, we isolated the lumbar spinal cord from mice and characterized them using Western blotting and immunofluorescence. The results showed that Dhrs4 expression in the spinal cord was upregulated with the progression of SOD1 G93A mice, and the upregulation of DHRS4 and its synergistic DHRS3 might be primarily associated with the activation of the complement cascade in the immune system (C1QA, C1QB, C1QC, C3, and ITGB2), which might be a novel mechanism that induces spinal neurodegeneration in ALS. We propose that DHRS4 and its synergistic DHRS3 are promising molecular markers for detecting ALS progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhu, Wei, Li, Chen, Jiang, Yuan and Xu.)

All-trans retinoic acid (ATRA), a ligand of retinoic acid receptors, could regulate various biological processes by activating retinoic acid signals. Recent studies suggested that ATRA displays multiple neuroprotective effects and thereby alleviates the disease progression in a variety of neurological diseases. Our previous studies found that the impaired retinoic acid signal decreased ALDH1A2, an essential synthetase of ATRA, in the spinal cord of ALS mice. Here, we evaluated the neuroprotective and neurorestorative effects of ATRA in a SOD1-G93A transgenic mice model of ALS. We administrated ATRA(3 mg/kg) daily from the onset stage to the progression stage for 5 weeks. Behavioral tests showed that ATRA improved the forelimb grip strength in ALS mice and may slow the disease progression, but not the body weight. ATRA could completely reverse the impaired retinoic acid receptor alpha (RARα) signal in the spinal cord of ALS mice. This effect was accompanied by enhancing the degradation of misfolded proteins via the ubiquitin-proteasome system, regulating the oxidative stress, inhibiting the astrocyte activation, and promoting the neurotrophic signal recovery. Our findings are the first to indicate that the damaged retinoic acid signal is involved in the pathogenesis of ALS, and ATRA could induce the functional neuroprotection via repairing the damaged retinoic acid signal.

Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, the brain stem, and the motor cortex. So far, there is still a lack of effective drugs. Nicotinamide adenine dinucleotide (NAD+) takes part in redox reactions and the NAD-dependent signaling pathway. The NAD+ decline is related with many neurological diseases, leading to the accumulation of neurotoxic protein in the central nervous system. Moreover, the NAD+ supplementation is shown to promote neural stem cells/neuronal precursor cells (NSCs/NPCs) pool maintenance. Regulatory mechanisms and functions of NAD+ metabolism in ALS are still unknown. Thus, we hypothesized the aggregation of human SOD1 toxic protein and the fate of NSCs/NPCs in the ALS disease could be improved by the administration of nicotinamide riboside (NR), an NAD+ precursor. In this study, we treated SOD1 G93A transgenic and wild-type mice by the oral administration of 20 mg/ml NR starting at 50 days of age. Effects of NR on the body weight, the motor function, the onset and the survival were assessed during the experiment. The expression of mutant hSOD1 protein, mitochondrial unfolded protein response (UPR mt ) related protein, mitophagy markers and NAD+ metabolism related protein were detected by immunoblotting. Effects of NR on the NSCs/NPCs in neurogenic niches of brain were identified by the immunofluorescence staining. Our investigation elucidated that the NR treatment exhibited better hanging wire endurance but did not postpone the onset or extend the life span of SOD1 G93A mice. Besides, we observed that the NR repletion promoted the clearance of mitochondrial hSOD1 neurotoxic protein. Meanwhile, the mitochondrial function pathway was disrupted in the brain of SOD1 G93A mice. What's more, we demonstrated that the inadequate function of NAD+ salvage synthesis pathway was the primary explanation behind the decline of NAD+, and the NR treatment enhanced the proliferation and migration of NSCs/NPCs in the brain of SOD1 G93A mice. At last, we found that levels of UPR mt related protein were significantly increased in the brain of SOD1 G93A mice after the NR treatment. In summary, these findings reveal that the administration of NR activates UPR mt signaling, modulates mitochondrial proteostasis and improves the adult neurogenesis in the brain of SOD1 G93A mice., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Evidences suggest that Cystatin C (Cys C) levels might be a biomarker in amyotrophic lateral sclerosis (ALS) diagnosis, but the conclusion is still in doubts. We conducted a systematic review and meta analysis of Cys C levels in cerebrospinal cord fluid (CSF) and peripheral blood of patients with ALS in order to further confirm whether or not Cys C levels is a biomarker in ALS diagnosis. The English relevant studies without year limitation were systematically searched in PubMed, EMBASE, Web of Science databases. The searched term contained "Amyotrophic Lateral Sclerosis" or "Motor Neuron Diseases" and "Cystatin C" and "Cerebrospinal fluid" or "CSF" or "Biomarker" or "Serum" or "Plasma" or "Blood". Observational studies reporting the associations between Cys C levels and ALS patients were selected to conduct a systematic review and meta analysis. Two reviewers performed the selection of this study independently. The Newcastle-Ottawa Scale assesses the quality and risk of bias of selected studies. Estimates were pooled using a random-effects model. The Cys C levels of CSF or peripheral blood in ALS patients compared with health controls (HCs) and several relevant neurodegenerative diseases (NDDs). Sixteen studies were included in our systematic review, 9 of them were selected to perform the meta analysis. Of these, eight studies measured Cys C levels in CSF and three studies measured it in blood. Cys C levels in CSF were significantly lower in ALS patients than in HCs (Hedge's g = -1.398, 95%CI: -2.43 to -0.36; p = 0.008), but there was no statistical difference between ALS patients and several relevant NDDs. No statistically significant difference in the Cys C levels of blood in the comparison between ALS and HCs. The correlation meta analysis presented no significant correlation between Cys C levels in CSF and age or disease duration respectively. Cys C levels significantly decrease in the CSF of ALS patients, but are not a specific biomarker for this disease. Cys C levels in CSF might be an auxiliary diagnostic biomarker of ALS., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Sporadic Parkinson's disease (sPD) and sporadic amyotrophic lateral sclerosis (sALS) are neurodegenerative diseases characterized by progressive and selective neuron death, with some genetic similarities. In order to investigate the genetic risk factors common to both sPD and sALS, we carried out a screen of risk alleles for sALS and related loci in 530 sPD patients and 530 controls from the Han population of Mainland China (HPMC). We selected 27 single-nucleotide polymorphisms in 10 candidate genes associated with sALS, and we performed allelotyping and genotyping to determine their frequencies in the study population as well as bioinformatics analysis to assess their functional significance in these diseases. The minor alleles of rs17115303 in DAB adaptor protein 1 (DAB1) gene and rs6030462 in protein tyrosine phosphatase receptor type T (PTPRT) gene were correlated with increased risk of both sPD and sALS. Polymorphisms of rs17115303 and rs6030462 were associated with alterations in transcription factor binding sites, secondary structures, long non-coding RNA interactions, and nervous system regulatory networks; these changes involved biological processes associated with neural cell development, differentiation, neurogenesis, migration, axonogenesis, cell adhesion, and metabolism of phosphate-containing compounds. Thus, variants of DAB1 gene (rs17115303) and PTPRT gene (rs6030462) are risk factors common to sPD and sALS in the HPMC. These findings provide insight into the molecular pathogenesis of both diseases and can serve as a basis for the development of targeted therapies. [ABSTRACT FROM AUTHOR]