Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

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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Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

Frontiers in Neurology ◽

10.3389/fneur.2021.645913 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jacqueline Dominguez ◽

Jeryl Tan Yu ◽

Yi Jayne Tan ◽

Arlene Ng ◽

Ma Fe De Guzman ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Positive Family History ◽

Clinical Manifestations ◽

The Philippines ◽

Chromosome 9 ◽

Genetic Modifiers ◽

Reading Frame ◽

Hexanucleotide Repeat ◽

Lateral Sclerosis

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

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Niclosamide Targets Inflammatory and Profibrotic Pathways in Amyotrophic Lateral Sclerosis

10.21203/rs.3.rs-138253/v1 ◽

2021 ◽

Author(s):

Martina Milani ◽

Eleonora Mammarella ◽

Simona Rossi ◽

Serena Lattante ◽

Mario Sabatelli ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cell Types ◽

Specific Protein ◽

Beneficial Effects ◽

Hexanucleotide Repeat ◽

Sporadic Als ◽

Als Patients ◽

Different Cell Types ◽

Lateral Sclerosis

Abstract BackgroundAn increasing number of studies evidence that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the up-regulation in ALS models of a gene called fibroblast-specific protein (FSP)-1 or S100A4, generally recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functioning, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.MethodsHere we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and sporadic ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.ResultsWe demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic and profibrotic pathways in ALS fibroblasts, and to interfere with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.ConclusionOur findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide that are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.

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Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

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The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms19103137 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3137 ◽

Cited By ~ 12

Author(s):

Anna Konopka ◽

Julie Atkin

Keyword(s):

Dna Damage ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Repeat Expansion ◽

Chromosome 9 ◽

Gene Encoding ◽

C9orf72 Repeat Expansion ◽

Reading Frame ◽

Early Onset Dementia ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.

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A-151 Cognitive Impairment in Amyotrophic Lateral Sclerosis

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.169 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1205-1205

Author(s):

Etiane Navarro ◽

Charles J Golden

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Impairment ◽

Literature Review ◽

Cognitive Impairments ◽

Empirical Literature ◽

Sporadic Als ◽

Neuropsychological Assessments ◽

Familial Als ◽

Als Patients ◽

Lateral Sclerosis

Abstract Objective Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease caused by degeneration of the upper and lower motor neurons. This literature review examines the recurring etiology of cognitive impairments in ALS through empirical literature. The current study explores ALS across different subtypes and potential cognitive impairments. Two classifications are primarily examined ALS, and ALS with frontotemporal dementia (ALS-FTD). Involving three categories: familial inheritance pattern, genetic mutation, or sporadic. Neuropsychological studies affirm cognitive impairments in individuals diagnosed with ALS and ALS-FTD. Data Selection Data was culled from the American Psychological Association (PsycInfo), PubMed, Google Scholar. Terms used in this literature review include cognitive impairment in ALS and ALS-FTD, executive function deficiencies in ALS, neuropsychology in ALS, neuropsychological deficits in ALS, neuropsychological assessments for ALS, cognitive impairments in familial ALS, genetic ALS, and sporadic ALS, familial ALS, sporadic ALS, genetic mutations involved in ALS. Search dates December 20–23 of 2020 and March 3–4 of 2021. A total of 40 studies were examined. Data Synthesis ALS-patients demonstrate a significant cognitive impairment. However, influencing comorbidities accompanying the disease may be contributing to these impairments. Researchers employed neuroimaging and neuropsychological batteries to further understand influencing factors involved in ALS and cognition. Conclusions Researchers now understand ALS as a multi-symptomatic disorder and acknowledge the presence of cognitive impairments at various encased levels. There are limitations in neuropsychological batteries that accommodate for executive dysfunctions observed in ALS patients. Future studies should explore neuropsychological assessments that accommodate for motor deficits and dysarthria when assessing cognitive impairment in ALS patients.

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Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200531 ◽

2021 ◽

Vol 8 (1) ◽

pp. 25-38

Author(s):

Marisa Cappella ◽

Pierre-François Pradat ◽

Giorgia Querin ◽

Maria Grazia Biferi

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Muscular Atrophy ◽

Monogenic Disease ◽

Sporadic Als ◽

Pathological Mechanism ◽

Huge Impact ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

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Incidence and Characteristics of Spinal Decompression Surgery after the Onset of Symptoms of Amyotrophic Lateral Sclerosis

Neurosurgery ◽

10.1227/01.neu.0000180028.64385.d3 ◽

2005 ◽

Vol 57 (5) ◽

pp. 984-989 ◽

Cited By ~ 18

Author(s):

Daniel Yoshor ◽

Arnett Klugh ◽

Stanley H. Appel ◽

Lanny J. Haverkamp

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Symptom Onset ◽

Spinal Surgery ◽

Foot Drop ◽

Spinal Decompression ◽

Sporadic Als ◽

Number Of Patients ◽

Als Patients ◽

The Impact ◽

Lateral Sclerosis

Abstract OBJECTIVE: The high incidence of spondylosis in patients at the mean age of onset (55.7 yr) of amyotrophic lateral sclerosis (ALS) can make recognition of ALS as a cause of weakness difficult. METHODS: To assess the impact of this diagnostic dilemma on neurosurgical practice, we performed a retrospective analysis of a database of more than 1500 patients with motor neuron disease. RESULTS: Of 1131 patients with typical, sporadic ALS, 47 (4.2%) underwent decompressive spinal surgery after the onset of retrospectively recognized symptoms of ALS. Among 55 operations in 47 ALS patients, 86% yielded no improvement, 9% produced minor improvement, and only 5% provided significant benefit. Cervical decompression was performed in 56%, lumbar in 42%, and thoracic in 2%. Foot drop was a symptom prompting surgery in 11 patients, and in 10, this finding was subsequently attributed solely to ALS. No differences between ALS patients who underwent spinal decompression and other ALS patients were noted regarding age at symptom onset, severity of impairment at time of diagnosis, or rate of disease progression. Not surprisingly, patients who had spinal surgery tended to have a longer interval between retrospectively recognized symptom onset and diagnosis of ALS. CONCLUSION: A small but significant number of patients with unrecognized ALS undergo spinal surgery that in retrospect may be inappropriate. The possibility of ALS must be considered in the evaluation of patients with weakness even in the presence of radiographic evidence of spondylosis and nerve root or spinal cord impingement.

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Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

Frontiers in Genetics ◽

10.3389/fgene.2021.740052 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaojing Gu ◽

Yongping Chen ◽

Qianqian Wei ◽

Yanbing Hou ◽

Bei Cao ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rare Variants ◽

Chinese Patients ◽

Causative Gene ◽

Missense Variants ◽

Whole Exome ◽

Sporadic Als ◽

Als Patients ◽

Lateral Sclerosis

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%.Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS.Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.

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Glial Cells in Amyotrophic Lateral Sclerosis

Neurology Research International ◽

10.1155/2011/718987 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 62

Author(s):

Jurate Lasiene ◽

Koji Yamanaka

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Glial Cells ◽

Motor Neurons ◽

Premature Death ◽

Active Role ◽

Sporadic Als ◽

Neuron Damage ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult motor neuron disease characterized by premature death of upper and lower motor neurons. Two percent of ALS cases are caused by the dominant mutations in the gene for superoxide dismutase 1 (SOD1) through a gain of toxic property of mutant protein. Genetic and chimeric mice studies using SOD1 models indicate that non-neuronal cells play important roles in neurodegeneration through non-cell autonomous mechanism. We review the contribution of each glial cell type in ALS pathology from studies of the rodent models and ALS patients. Astrogliosis and microgliosis are not only considerable hallmarks of the disease, but the intensity of microglial activation is correlated with severity of motor neuron damage in human ALS. The impaired astrocytic functions such as clearance of extracellular glutamate and release of neurotrophic factors are implicated in disease. Further, the damage within astrocytes and microglia is involved in accelerated disease progression. Finally, other glial cells such as NG2 cells, oligodendrocytes and Schwann cells are under the investigation to determine their contribution in ALS. Accumulating knowledge of active role of glial cells in the disease should be carefully applied to understanding of the sporadic ALS and development of therapy targeted for glial cells.

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Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2011.006 ◽

2011 ◽

Vol 6 (1) ◽

Author(s):

Gisella Gargiulo Monachelli ◽

Maria Meyer ◽

Gabriel Rodríguez ◽

Laura Garay ◽

Roberto E. Sica ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Prognostic Factors ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Sporadic Als ◽

Bulbar Onset ◽

Als Patients ◽

Short Time ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

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