Journal articles: 'ALS pathogenesis'

1

Silani, V. "ALS: Current theories of pathogenesis." Electroencephalography and Clinical Neurophysiology 103, no. 1 (July 1997): 17–18. http://dx.doi.org/10.1016/s0013-4694(97)87981-7.

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McCauley, Madelyn E., and Robert H. Baloh. "Inflammation in ALS/FTD pathogenesis." Acta Neuropathologica 137, no. 5 (November 21, 2018): 715–30. http://dx.doi.org/10.1007/s00401-018-1933-9.

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Abe, Koji. "Clinical Features, Pathogenesis, and Therapy for ALS." Spinal Surgery 26, no. 3 (2012): 270–77. http://dx.doi.org/10.2531/spinalsurg.26.270.

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Beal, M. F. "Mitochondria and the pathogenesis of ALS." Brain 123, no. 7 (July 1, 2000): 1291–92. http://dx.doi.org/10.1093/brain/123.7.1291.

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Onodera, Osamu. "Molecular pathogenesis of ALS in TDP43 era." Rinsho Shinkeigaku 53, no. 11 (2013): 1077–79. http://dx.doi.org/10.5692/clinicalneurol.53.1077.

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Li, Yun R., Oliver D. King, James Shorter, and Aaron D. Gitler. "Stress granules as crucibles of ALS pathogenesis." Journal of Cell Biology 201, no. 3 (April 29, 2013): 361–72. http://dx.doi.org/10.1083/jcb.201302044.

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Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.

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Choi, Hyun-Jun, Sun Joo Cha, Jang-Won Lee, Hyung-Jun Kim, and Kiyoung Kim. "Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis." Brain Sciences 10, no. 10 (September 26, 2020): 675. http://dx.doi.org/10.3390/brainsci10100675.

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Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

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Rossi, Simona, Mauro Cozzolino, and Maria Teresa Carrì. "OldversusNew Mechanisms in the Pathogenesis of ALS." Brain Pathology 26, no. 2 (March 2016): 276–86. http://dx.doi.org/10.1111/bpa.12355.

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Carrì, Maria Teresa, Nadia D’Ambrosi, and Mauro Cozzolino. "Pathways to mitochondrial dysfunction in ALS pathogenesis." Biochemical and Biophysical Research Communications 483, no. 4 (February 2017): 1187–93. http://dx.doi.org/10.1016/j.bbrc.2016.07.055.

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Yang, Xiaoming, Yanan Ji, Wei Wang, Lilei Zhang, Zehao Chen, Miaomei Yu, Yuntian Shen, Fei Ding, Xiaosong Gu, and Hualin Sun. "Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies." Antioxidants 10, no. 7 (June 24, 2021): 1012. http://dx.doi.org/10.3390/antiox10071012.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.

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Perrot, Rodolphe, and Jean-Pierre Julien. "Maldistribution of Neurofilaments, Disease Pathogenesis, and Amyotrophic Lateral Sclerosis." US Neurology 05, no. 02 (2010): 30. http://dx.doi.org/10.17925/usn.2010.05.02.30.

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Accumulations of neuronal intermediate filaments (IFs) are a characteristic of many human neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, IF formation and the contribution of IF aggregates to the pathogenesis of ALS remain unclear. Here, we review the possible mechanisms underlying the formation of IF accumulations and the mouse models that have been used to investigate the role of IF proteins in ALS pathogenesis.

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Munoz, D. G. "FUS mutations in sporadic juvenile ALS: Another step toward understanding ALS pathogenesis." Neurology 75, no. 7 (July 28, 2010): 584–85. http://dx.doi.org/10.1212/wnl.0b013e3181ed9ee4.

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Lualdi, Marta, Adeena Shafique, Edoardo Pedrini, Luisa Pieroni, Viviana Greco, Massimo Castagnola, Giorgia Cucina, et al. "C9ORF72 Repeat Expansion Affects the Proteome of Primary Skin Fibroblasts in ALS." International Journal of Molecular Sciences 22, no. 19 (September 27, 2021): 10385. http://dx.doi.org/10.3390/ijms221910385.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.

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Rentzos, Michael, Maria Elepthera Evangelopoulos, Eleni Sereti, Vassiliki Zouvelou, Styliani Marmara, Theodoros Alexakis, and Ioannis Evdokimidis. "Humoral immune activation in amyotrophic lateral sclerosis patients." Neurology International 5, no. 1 (February 11, 2013): 3. http://dx.doi.org/10.4081/ni.2013.e3.

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There is evidence that immunological factors may involved in the pathogenetic mecha- nisms of amyotrophic lateral sclerosis (ALS). Few studies to date have explored the status of the humoral immune response in patients with ALS. We examined the presence of humoral immune activation in ALS patients, serum immunoglobulins (IgG, IgA and IgM) levels were measured in 36 patients with ALS and 35 normal controls. Serum IgG, IgM and IgA levels were not significantly different in our ALS patients compared with the control group (P=ns). No correlations of serum IgG, IgM and IgA concentrations with duration, severity of the disease or the clinical form of onset (bulbar or spinal) were found in our ALS patients. Our results do not suggest a humoral immune activation in ALS patients. This does not exclude that immunological mechanisms may be involved in ALS pathogenesis.

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Liu, Dingsheng, Xiaojia Zuo, Peng Zhang, Rui Zhao, Donglin Lai, Kaijie Chen, Yuru Han, et al. "The Novel Regulatory Role of lncRNA-miRNA-mRNA Axis in Amyotrophic Lateral Sclerosis: An Integrated Bioinformatics Analysis." Computational and Mathematical Methods in Medicine 2021 (April 15, 2021): 1–12. http://dx.doi.org/10.1155/2021/5526179.

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that primarily affects motor neurons, causing muscle atrophy, bulbar palsy, and pyramidal tract signs. However, the aetiology and pathogenesis of ALS have not been elucidated to date. In this study, a competitive endogenous RNA (ceRNA) network was constructed by analyzing the expression profiles of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) that were matched by 7 ALS samples and 4 control samples, and then a protein-protein interaction (PPI) network was constructed to identify the genes related to ALS. Gene Ontology (GO) was used to study the potential functions of differentially expressed mRNAs (DEmRNAs) in the ceRNA network. For the ALS and control groups, 247177 potential lncRNA-mRNA ceRNA relationship pairs were screened. Analysis of significant relationship pairs demonstrated that the PPI modules formed by the MALAT1-regulated SYNRG, ITSN2, PICALM, AP3B1, and AAK1 genes may play important roles in the pathogenesis of ALS, and these results may help to characterize the pathogenesis of ALS.

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Nowicka, Natalia, Kamila Szymańska, Judyta Juranek, Kamila Zglejc-Waszak, Agnieszka Korytko, Michał Załęcki, Małgorzata Chmielewska-Krzesińska, Krzysztof Wąsowicz, and Joanna Wojtkiewicz. "The Involvement of RAGE and Its Ligands during Progression of ALS in SOD1 G93A Transgenic Mice." International Journal of Molecular Sciences 23, no. 4 (February 16, 2022): 2184. http://dx.doi.org/10.3390/ijms23042184.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive degeneration of upper and lower motor neurons that causes paralysis and muscle atrophy. The pathogenesis of the disease is still not elucidated. Receptor for Advanced Glycation End Product (RAGE) is a major component of the innate immune system and has implications in ALS pathogenesis. Multiple studies suggest the role of RAGE and its ligands in ALS. RAGE and its ligands are overexpressed in human and murine ALS motor neurons, astrocytes, and microglia. Here, we demonstrated the expression of RAGE and its ligands during the progression of the disease in the transgenic SOD1 G93A mouse lumbar spinal cord. We observed the highest expression of HMGB1 and S100b proteins at ALS onset. Our results highlight the potential role of RAGE and its ligands in ALS pathogenesis and suggest that some of the RAGE ligands might be used as biomarkers in early ALS diagnosis and potentially be useful in targeted therapeutic interventions at the early stage of this devastating disease.

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Sanhueza, Mario, Andrea Chai, Colin Smith, Brett A. McCray, T. Ian Simpson, J. Paul Taylor, and Giuseppa Pennetta. "Network Analyses Reveal Novel Aspects of ALS Pathogenesis." PLOS Genetics 11, no. 3 (March 31, 2015): e1005107. http://dx.doi.org/10.1371/journal.pgen.1005107.

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McCombe, Pamela A., Robert D. Henderson, Aven Lee, John D. Lee, Trent M. Woodruff, Restuadi Restuadi, Allan McRae, Naomi R. Wray, Shyuan Ngo, and Frederik J. Steyn. "Gut microbiota in ALS: possible role in pathogenesis?" Expert Review of Neurotherapeutics 19, no. 9 (May 29, 2019): 785–805. http://dx.doi.org/10.1080/14737175.2019.1623026.

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TANAKA, F., J. I. NIWA, S. ISHIGAKI, M. KATSUNO, M. WAZA, M. YAMAMOTO, M. DOYU, and G. SOBUE. "Gene Expression Profiling toward Understanding of ALS Pathogenesis." Annals of the New York Academy of Sciences 1086, no. 1 (November 1, 2006): 1–10. http://dx.doi.org/10.1196/annals.1377.011.

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Ravits, John. "Focality, stochasticity and neuroanatomic propagation in ALS pathogenesis." Experimental Neurology 262 (December 2014): 121–26. http://dx.doi.org/10.1016/j.expneurol.2014.07.021.

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Eisen, Andrew, Bhanu Pant, and Heather Stewart. "Cortical Excitability in Amyotrophic Lateral Sclerosis: A Clue to Pathogenesis." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 20, no. 1 (February 1993): 11–16. http://dx.doi.org/10.1017/s031716710004734x.

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ABSTRACT:Motor evoked potentials (MEPs) were recorded from selected non-wasted, non-denervated hand muscles in 40 patients with Amyotrophic Lateral Sclerosis (ALS) with both upper and lower motor neuron signs. In most the compound muscle action potential (CMAP) of the target muscle was normal. Compared to the control group, cortical threshold in ALS varied considerably and there was a significant (r2= 0.702) inverse, exponential, correlation between cortical threshold and MEP/CMAP ratio. There was a linear correlation between threshold and disease duration (r2= 0.66) so that early in the disease threshold was normal and later the motor cortex could not be stimulated. It is suggested that early in ALS normal threshold reflects glutamate-induced hyper-excitability of the corticomotoneuron. The findings lend support to the hypothesis that ALS is primarily a disease of the corticomotoneuron.

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Menounos, Spiro, Philip M. Hansbro, Ashish D. Diwan, and Abhirup Das. "Pathophysiological Correlation between Cigarette Smoking and Amyotrophic Lateral Sclerosis." NeuroSci 2, no. 2 (April 20, 2021): 120–34. http://dx.doi.org/10.3390/neurosci2020008.

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Cigarette smoke (CS) has been consistently demonstrated to be an environmental risk factor for amyotrophic lateral sclerosis (ALS), although the molecular pathogenic mechanisms involved are yet to be elucidated. Here, we propose different mechanisms by which CS exposure can cause sporadic ALS pathogenesis. Oxidative stress and neuroinflammation are widely implicated in ALS pathogenesis, with blood–spinal cord barrier disruption also recognised to be involved in the disease process. In addition, immunometabolic, epigenetic and microbiome alterations have been implicated in ALS recently. Identification of the underlying pathophysiological mechanisms that underpin CS-associated ALS will drive future research to be conducted into new targets for treatment.

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Sun, Hualin, Ming Li, Yanan Ji, Jianwei Zhu, Zehao Chen, Lilei Zhang, Chunyan Deng, et al. "Identification of Regulatory Factors and Prognostic Markers in Amyotrophic Lateral Sclerosis." Antioxidants 11, no. 2 (February 1, 2022): 303. http://dx.doi.org/10.3390/antiox11020303.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to muscle atrophy, paralysis and even death. Immune disorder, redox imbalance, autophagy disorder, and iron homeostasis disorder have been shown to play critical roles in the pathogenesis of ALS. However, the exact pathogenic genes and the underlying mechanism of ALS remain unclear. The purpose of this study was to screen for pathogenic regulatory genes and prognostic markers in ALS using bioinformatics methods. We used Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and expression regulation network analysis to investigate the function of differentially expressed genes in the nerve tissue, lymphoid tissue, and whole blood of patients with ALS. Our results showed that the up-regulated genes were mainly involved in immune regulation and inflammation, and the down-regulated genes were mainly involved in energy metabolism and redox processes. Eleven up-regulated transcription factors (CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, and FOXJ1) and one down-regulated transcription factor (NOG) in the nerve tissue of patients with ALS likely play important regulatory roles in the pathogenesis of ALS. Based on construction and evaluation of the ALS biomarker screening model, cluster analysis of the identified characteristic genes, univariate Cox proportional hazards regression analysis, and the random survival forest algorithm, we found that MAEA, TPST1, IFNGR2, and ALAS2 may be prognostic markers regarding the survival of ALS patients. High expression of MAEA, TPST1, and IFNGR2 and low expression of ALAS2 in ALS patients may be closely related to short survival of ALS patients. Taken together, our results indicate that immune disorders, inflammation, energy metabolism, and redox imbalance may be the important pathogenic factors of ALS. CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, FOXJ1, and NOG may be important regulatory factors linked to the pathogenesis of ALS. MAEA, TPST1, IFNGR2, and ALAS2 are potential important ALS prognostic markers. Our findings provide evidence on the pathogenesis of ALS, potential targets for the development of new drugs for ALS, and important markers for predicting ALS prognosis.

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Gambino, Caterina Maria, Anna Maria Ciaccio, Bruna Lo Sasso, Rosaria Vincenza Giglio, Matteo Vidali, Luisa Agnello, and Marcello Ciaccio. "The Role of TAR DNA Binding Protein 43 (TDP-43) as a Candi-Date Biomarker of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis." Diagnostics 13, no. 3 (January 23, 2023): 416. http://dx.doi.org/10.3390/diagnostics13030416.

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Background: TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly supports the pathogenetic role of TDP-43 in ALS pathogenesis, the role of TDP-43 as a biomarker of ALS is controversial. We performed a systematic review and meta-analysis to assess the diagnostic performance of TDP-43 for ALS. Methods: Relevant publications were identified by a systematic literature search on PubMed and Web of Science from their inception to April 8, 2022. Results: Seven studies, including 472 individuals, of whom 254 had ALS according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, met the inclusion criteria for our meta-analysis. According to the random-effects model, CSF TDP-43 levels are higher in ALS patients compared with control groups. Conclusions: CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions.

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Dodge, James C., Christopher M. Treleaven, Joshua Pacheco, Samantha Cooper, Channa Bao, Marissa Abraham, Mandy Cromwell, et al. "Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis." Proceedings of the National Academy of Sciences 112, no. 26 (June 8, 2015): 8100–8105. http://dx.doi.org/10.1073/pnas.1508767112.

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Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.

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Hosaka, Takashi, Hiroshi Tsuji, and Shin Kwak. "Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets." Cells 12, no. 10 (May 22, 2023): 1443. http://dx.doi.org/10.3390/cells12101443.

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Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca2+ influx through Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.

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Trojsi, Francesca, Giulia D’Alvano, Simona Bonavita, and Gioacchino Tedeschi. "Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?" International Journal of Molecular Sciences 21, no. 10 (May 21, 2020): 3647. http://dx.doi.org/10.3390/ijms21103647.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

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Vonk, Willianne I. M., and Leo W. J. Klomp. "Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1322–28. http://dx.doi.org/10.1042/bst0361322.

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ALS (amyotrophic lateral sclerosis) is a devastating progressive neurodegenerative disorder resulting in selective degeneration of motor neurons in brain and spinal cord and muscle atrophy. In approx. 2% of all cases, the disease is caused by a mutation in the Cu,Zn-superoxide dismutase (SOD1) gene. The transition metals zinc and copper regulate SOD1 protein stability and activity, and disbalance of the homoeostasis of these metals has therefore been implicated in the pathogenesis of ALS. Recent data strengthen the hypothesis that these transition metals are excellent potential targets to develop an effective therapy for ALS.

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Duranti, Elisa, and Chiara Villa. "Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 24, no. 1 (December 31, 2022): 704. http://dx.doi.org/10.3390/ijms24010704.

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Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.

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Julien, Jean-Pierre. "A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis." Biochemistry and Cell Biology 73, no. 9-10 (September 1, 1995): 593–97. http://dx.doi.org/10.1139/o95-064.

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Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of motor neurons, characterized by abnormal accumulation of neurofilaments (NFs) in perikarya and proximal axons. Two lines of evidence suggest that neurofilament accumulation can play a crucial role in ALS pathogenesis. First, transgenic mouse models overexpressing NF proteins were found to develop motor neuron degeneration and, second, variant alleles of the NF heavy-subunit (NF-H) gene have been found in some human ALS patients. Our axonal transport studies with transgenic mice overexpressing the human NF-H gene, a model of ALS, revealed defects of intracellular transport not only for neurofilament proteins but also for other cytoskeletal proteins and organelles such as mitochondria. Therefore, we propose that neurofilament accumulation in mice causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS.Key words: amyotrophic lateral sclerosis, neurofilaments, transgenic mice, axonal transport.

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Le Gall, L., W. J. Duddy, J. Lainé, S. Roquevière, F. Ratti, Z. G. Ouandaogo, L. Robelin, et al. "Secretion of toxic exosomes by muscle cells of ALS patients: role in ALS pathogenesis." Neuromuscular Disorders 27 (March 2017): S32. http://dx.doi.org/10.1016/s0960-8966(17)30313-9.

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Alessenko, Alisa V., Uliana A. Gutner, and Maria A. Shupik. "Involvement of Lipids in the Pathogenesis of Amyotrophic Lateral Sclerosis." Life 13, no. 2 (February 12, 2023): 510. http://dx.doi.org/10.3390/life13020510.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons. To study its underlying mechanisms, a variety of models are currently used at the cellular level and in animals with mutations in multiple ALS associated genes, including SOD1, C9ORF72, TDP-43, and FUS. Key mechanisms involved in the disease include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammatory, and immune reactions. In addition, significant metabolism alterations of various lipids classes, including phospholipids, fatty acids, sphingolipids, and others have been increasingly recognized. Recently, the mechanisms of programmed cell death (apoptosis), which may be responsible for the degeneration of motor neurons observed in the disease, have been intensively studied. In this context, sphingolipids, which are the most important sources of secondary messengers transmitting signals for cell proliferation, differentiation, and apoptosis, are gaining increasing attention in the context of ALS pathogenesis given their role in the development of neuroinflammatory and immune responses. This review describes changes in lipids content and activity of enzymes involved in their metabolism in ALS, both summarizing current evidence from animal models and clinical studies and discussing the potential of new drugs among modulators of lipid metabolism enzymes.

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Zhang, Yi, Jiayu Gu, and Qiming Sun. "Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis." Cells 10, no. 9 (August 30, 2021): 2247. http://dx.doi.org/10.3390/cells10092247.

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Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.

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Cheng, Ching-Wei, Meng-Jau Lin, and Che-Kun James Shen. "Rapamycin alleviates pathogenesis of a newDrosophilamodel of ALS-TDP." Journal of Neurogenetics 29, no. 2-3 (July 3, 2015): 59–68. http://dx.doi.org/10.3109/01677063.2015.1077832.

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Kawahara, Yukio. "Implications of microRNA dysfunction in the pathogenesis of ALS." Rinsho Shinkeigaku 50, no. 11 (2010): 979–81. http://dx.doi.org/10.5692/clinicalneurol.50.979.

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Hirano, M. "VAPB: New genetic clues to the pathogenesis of ALS." Neurology 70, no. 14 (March 31, 2008): 1161–62. http://dx.doi.org/10.1212/01.wnl.0000307756.15383.fc.

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Yerbury, Justin J., Natalie E. Farrawell, and Luke McAlary. "Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis." Trends in Neurosciences 43, no. 5 (May 2020): 274–84. http://dx.doi.org/10.1016/j.tins.2020.03.002.

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Swarup, Vivek, and Jean-Pierre Julien. "ALS pathogenesis: Recent insights from genetics and mouse models." Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, no. 2 (March 2011): 363–69. http://dx.doi.org/10.1016/j.pnpbp.2010.08.006.

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Vatsavayai, Sarat C., Alissa L. Nana, Jennifer S. Yokoyama, and William W. Seeley. "C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies." Acta Neuropathologica 137, no. 1 (October 27, 2018): 1–26. http://dx.doi.org/10.1007/s00401-018-1921-0.

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Ferri, Alberto, and Roberto Coccurello. "What is “Hyper” in the ALS Hypermetabolism?" Mediators of Inflammation 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/7821672.

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The progressive and fatal loss of upper (brain) and lower (spinal cord) motor neurons and muscle denervation concisely condenses the clinical picture of amyotrophic lateral sclerosis (ALS). Despite the multiple mechanisms believed to underlie the selective loss of motor neurons, ALS aetiology remains elusive and obscure. Likewise, there is also a cluster of alterations in ALS patients in which muscle wasting, body weight loss, eating dysfunction, and abnormal energy dissipation coexist. Defective energy metabolism characterizes the ALS progression, and such paradox of energy balance stands as a challenge for the understanding of ALS pathogenesis. The hypermetabolism in ALS will be examined from tissue-specific energy imbalance (e.g., skeletal muscle) to major energetic pathways (e.g., AMP-activated protein kinase) and whole-body energy alterations including glucose and lipid metabolism, nutrition, and potential involvement of interorgan communication. From the point of view here expressed, the hypermetabolism in ALS should be evaluated as a magnifying glass through which looking at the ALS pathogenesis is from a different perspective in which defective metabolism can disclose novel mechanistic interpretations and lines of intervention.

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Andrew, Eisen, and Krieger Charles. "Pathogenic Mechanisms in Sporadic Amyotrophic Lateral Sclerosis." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 20, no. 4 (November 1993): 286–96. http://dx.doi.org/10.1017/s0317167100048198.

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ABSTRACT:In recognition of the 100th anniversary of Charcot’s death we have reviewed possible pathogenic mechanisms in amyotrophic lateral sclerosis (ALS). Advances in the last 5 years in molecular biology and genetics have identified mutations in the cytosolic dismutase (SODI) gene in some patients with familial ALS raising the possibility that oxidative stress may be involved in the pathogenesis. An excitotoxic pathogenesis has been implicated based on elevated plasma and CSF levels of amino acids and altered contents of amino acids in the nervous system of ALS patients and changes in the number of excitatory amino acid receptors. ALS sera containing antibodies to L-type calcium channels and the development of immune mediated lower and upper and lower motor neuron models have revitalized research efforts focusing on an immune basis for ALS. Other pathogenic mechanisms which have been the subject of recent research include elemental toxicity, apoptosis and programmed cell death and possibly a deficiency or abnormality in growth factors. Pathogenic processes for ALS must account for an increasing incidence of ALS, male preponderance, and the selective vulnerability of the corticomotoneuronal system.

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Otomo, Asako, Lei Pan, and Shinji Hadano. "Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases." Neurology Research International 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/498428.

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Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

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Turnbull, John. "Why is ALS so Difficult to Treat?" Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 41, no. 2 (March 2014): 144–55. http://dx.doi.org/10.1017/s0317167100016516.

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Amyotrophic lateral sclerosis (ALS) is proving intractable. Difficulties in pre-clinical studies contribute in small measure to this futility, but the chief reason for failure is an inadequate understanding of disease pathogenesis. Many acquired and inherited processes have been advanced as potential causes of ALS but, while they may predispose to disease, it seems increasingly likely that none leads directly to ALS. Rather, two recent overlapping considerations, both involving aberrant protein homeostasis, may provide a better explanation for a common disease phenotype and a common terminal pathogenesis. If so, therapeutic approaches will need to be altered and carefully nuanced, since protein homeostasis is essential and highly conserved. Nonetheless, these considerations provide new optimism in a difficult disease which has hitherto defied treatment.

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Carmine, Ungaro, and Sprovieri Teresa. "Mercury toxicity and amyotrophic lateral sclerosis." Journal of Neuroscience and Neurological Disorders 7, no. 1 (March 23, 2023): 011–13. http://dx.doi.org/10.29328/journal.jnnd.1001074.

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Recent clinical, experimental and epidemiological studies report that ALS is thought possibly due to a multi-stage process, arising from a combination of genetic susceptibility and environmental factors, which alone or superimposed, perhaps on genetic polymorphism yet to be identified, may contribute to the incidence rate of sporadic ALS. In particular, a large amount of evidence suggests that mercury is toxic to motor neurons and may be a risk factor for ALS, playing a part in its pathogenesis. In fact, there have been case reports of ALS or ALS-like symptoms associated with mercury exposure, thus raising the possibility that mercury could be one of the non-genetic factors of the multistep process that is thought to underlie ALS. In order to give recent elucidations on the putative relationship between mercury exposure and ALS, we reviewed all the papers reported in the literature and published on Pubmed from 2006 to 2022. Despite a number of pathogenetic mechanisms that have been linked to mercury, evidence linking exposure to mercury to ALS is not consistent and discordant and, based on the evaluation of the articles, which emerged from our analysis that to date no convincing correlation between mercury and ALS has been established and no conclusive evidence has been enlightened suggesting increased mercury exposure is associated with ALS.

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Berrone, Elena, Giovanna Chiorino, Francesca Guana, Valerio Benedetti, Claudia Palmitessa, Marina Gallo, Andrea Calvo, et al. "SOMAscan Proteomics Identifies Novel Plasma Proteins in Amyotrophic Lateral Sclerosis Patients." International Journal of Molecular Sciences 24, no. 3 (January 18, 2023): 1899. http://dx.doi.org/10.3390/ijms24031899.

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Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by the interplay of genetic and environmental factors for which, despite decades of intense research, diagnosis remains rather delayed, and most therapeutic options fail. Therefore, unravelling other potential pathogenetic mechanisms and searching for reliable markers are high priorities. In the present study, we employ the SOMAscan assay, an aptamer-based proteomic technology, to determine the circulating proteomic profile of ALS patients. The expression levels of ~1300 proteins were assessed in plasma, and 42 proteins with statistically significant differential expression between ALS patients and healthy controls were identified. Among these, four were upregulated proteins, Thymus- and activation-regulated chemokine, metalloproteinase inhibitor 3 and nidogen 1 and 2 were selected and validated by enzyme-linked immunosorbent assays in an overlapping cohort of patients. Following statistical analyses, different expression patterns of these proteins were observed in the familial and sporadic ALS patients. The proteins identified in this study might provide insight into ALS pathogenesis and represent potential candidates to develop novel targeted therapies.

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Marc, Gotkine, Rozenstein Leah, Einstein Ofira, Abramsky Oded, Argov Zohar, and Rosenmann Hanna. "Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/845345.

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Objective. Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model.Methods. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose.Results. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters.Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.

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De Marchi, Fabiola, Giacomo Tondo, Lucia Corrado, Federico Menegon, Davide Aprile, Matteo Anselmi, Sandra D’Alfonso, Cristoforo Comi, and Letizia Mazzini. "Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants." Genes 14, no. 8 (August 21, 2023): 1658. http://dx.doi.org/10.3390/genes14081658.

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Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10–15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.

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Cai, Qing, Mengya Li, and Qifang Li. "Sleep‐based therapy: A new treatment for amyotrophic lateral sclerosis." Brain Science Advances 7, no. 3 (September 2021): 155–62. http://dx.doi.org/10.26599/bsa.2021.9050010.

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Amyotrophic lateral sclerosis (ALS) is a worldwide problem with no effective treatment. Patients usually die of respiratory failure. The basic pathological process of ALS is the degeneration and necrosis of motor neurons. Neuroglial cell dysfunction is considered closely related to the development of ALS. Sleep plays an important role in repairing the nervous system, and sleep disorders can worsen ALS. Herein, we review the pathogenesis of ALS and the neuroprotective mechanism of sleep‐based therapy. Sleep‐based therapy could be a potential strategy to treat ALS.

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Gros-Louis, François, Roxanne Larivière, Geneviève Gowing, Sandra Laurent, William Camu, Jean-Pierre Bouchard, Vincent Meininger, Guy A. Rouleau, and Jean-Pierre Julien. "A Frameshift Deletion in Peripherin Gene Associated with Amyotrophic Lateral Sclerosis." Journal of Biological Chemistry 279, no. 44 (August 17, 2004): 45951–56. http://dx.doi.org/10.1074/jbc.m408139200.

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Peripherin is a neuronal intermediate filament associated with inclusion bodies in motor neurons of patients with amyotrophic lateral sclerosis (ALS). A possible peripherin involvement in ALS pathogenesis has been suggested based on studies with transgenic mouse overexpressors and with a toxic splicing variant of the mouse peripherin gene. However, the existence of peripherin gene mutations in human ALS has not yet been documented. Therefore, we screened for sequence variants of the peripherin gene (PRPH) in a cohort of ALS patients including familial and sporadic cases. We identified 18 polymorphic variants ofPRPHdetected in both ALS and age-matched control populations. Two additionalPRPHvariants were discovered in ALS cases but not in 380 control individuals. One variant consisted of a nucleotide insertion in intron 8 (PRPHIVS8–36insA), whereas the other one consisted of a 1-bp deletion within exon 1 (PRPH228delC), predicting a truncated peripherin species of 85 amino acids. Remarkably, expression of this frameshift peripherin mutant in SW13 cells resulted in disruption of neurofilament network assembly. These results suggest thatPRPHmutations may be responsible for a small percentage of ALS, cases and they provide further support of the view that neurofilament disorganization may contribute to pathogenesis.

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Rey, Federica, Stefania Marcuzzo, Silvia Bonanno, Matteo Bordoni, Toniella Giallongo, Claudia Malacarne, Cristina Cereda, Gian Vincenzo Zuccotti, and Stephana Carelli. "LncRNAs Associated with Neuronal Development and Oncogenesis Are Deregulated in SOD1-G93A Murine Model of Amyotrophic Lateral Sclerosis." Biomedicines 9, no. 7 (July 13, 2021): 809. http://dx.doi.org/10.3390/biomedicines9070809.

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Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease caused in 10% of cases by inherited mutations considered “familial”. An ever-increasing amount of evidence is showing a fundamental role for RNA metabolism in ALS pathogenesis, and long non-coding RNAs (lncRNAs) appear to play a role in ALS development. Here, we aim to investigate the expression of a panel of lncRNAs (linc-Enc1, linc–Brn1a, linc–Brn1b, linc-p21, Hottip, Tug1, Eldrr, and Fendrr) which could be implicated in early phases of ALS. Via Real-Time PCR, we assessed their expression in a murine familial model of ALS (SOD1-G93A mouse) in brain and spinal cord areas of SOD1-G93A mice in comparison with that of B6.SJL control mice, in asymptomatic (week 8) and late-stage disease (week 18). We highlighted a specific area and pathogenetic-stage deregulation in each lncRNA, with linc-p21 being deregulated in all analyzed tissues. Moreover, we analyzed the expression of their human homologues in SH-SY5Y-SOD1-WT and SH-SY5Y-SOD1-G93A, observing a profound alteration in their expression. Interestingly, the lncRNAs expression in our ALS models often resulted opposite to that observed for the lncRNAs in cancer. These evidences suggest that lncRNAs could be novel disease-modifying agents, biomarkers, or pathways affected by ALS neurodegeneration.

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Journal articles on the topic 'ALS pathogenesis'

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