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![Racial/ethnic difference of amyotrophic lateral sclerosis (ALS) causative genes [28, 29, 93]. The pie charts of ALS causative genes in Europeans and Japan are shown, color-coded with SOD1, TARDBP, FUS, C9ORF72, and not determined (ND) in these four genes. Mutations were identified in 55.5% of Europeans with familial ALS and 43.6% of Japanese individuals with familial ALS. In sporadic ALS, only 7.4% of mutations were identified in Europe and 2.9% in Japan. The difference between European and Japanese is largely due to the difference in the frequency of C9ORF72 mutation, SOD1, and FUS being more common in Japanese and TARDBP being more common in European](publication/361256136/figure/fig1/AS:1166486186016770@1655123387247/Racial-ethnic-difference-of-amyotrophic-lateral-sclerosis-ALS-causative-genes-28-29.png)
Racial/ethnic difference of amyotrophic lateral sclerosis (ALS) causative genes [28, 29, 93]. The pie charts of ALS causative genes in Europeans and Japan are shown, color-coded with SOD1, TARDBP, FUS, C9ORF72, and not determined (ND) in these four genes. Mutations were identified in 55.5% of Europeans with familial ALS and 43.6% of Japanese individuals with familial ALS. In sporadic ALS, only 7.4% of mutations were identified in Europe and 2.9% in Japan. The difference between European and Japanese is largely due to the difference in the frequency of C9ORF72 mutation, SOD1, and FUS being more common in Japanese and TARDBP being more common in European
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Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes o...
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Context 1
... results of the analysis of causative genes in European and Japanese are shown in Fig. 1. Mutations in SOD1, TARDBP, FUS, and C9ORF72 were color-coded according to a review of the literature [27,29], and data in Japan is modified from our previous study [28]. Mutations not determined (ND) in these four genes were also color-coded. Mutations were identified in 55.5% of Europeans with familial ALS and 43.6% of Japanese ...
Context 2
... novo mutations in sporadic ALS The reported incidence of some ALS-associated variants in familial and sporadic ALS is different among causative genes. Moreover, 3-16% of sporadic ALS cases have monogenetic etiology (Fig. 1) [28,29,93,119]. Others have reported that 21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS [120]. There could be several other cases of sporadic ALS with SOD1 mutations; however, either (a) DNA analysis of the parents showed one of them to be an ...
Citations
... However, SOD1 mutations account for a very small proportion (~2%) of overall cases of ALS 18 . ...
A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all (∼97%) cases (familial and sporadic) have in common is cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs.
We used the TDP-43(ΔNLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.
... Although most currently available treatments have not been clearly shown to have a clinically beneficial effect, several clinical trials of ASOs are underway, focusing on SOD1, FUS and C9orf72. These emphasize the importance to refer all ALS patients for genetic testing, and give them hope for the future [2,23]. ...
... The second major motivation for genetic testing among our cohort was disease prevention in future generations [23]. Notably, following the genetic testing results, several families requested PGD. ...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.
We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018–2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.
We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.
... Therefore, attempts to elucidate disease mechanisms and pathogenic genetic variants are essential. Previous research has identified more than 30 genes associated with ALS, highlighting four genes, SOD1, TARDBP (TDP-43), C9ORF72, and FUS, for harbouring pathogenic mutations, which cause the greatest number of ALS cases [10][11][12][13]. Although these four genes have been identified as major ALS-associated genes, a 2017 meta-analysis study demonstrated that within European and Asian populations, these genes only contribute to 47.7% and 5.2% of familial and sporadic cases, respectively [14]. ...
Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.
... Its relentless progression eventually leads to a complete loss of motor function, and results in fatality within 2-5 years after initial diagnosis. More than 30 genes have been identified as causative or diseasemodifying, with pathogenic variants in C9ORF72, SOD1, TARDBP, FUS and NEK1 occurring most frequently (Akcimen et al., 2023;Suzuki et al., 2023;Taylor et al., 2016). However, the underlying etiology of ALS remains elusive, and treatment options for the majority of sporadic patients remain limited. ...
UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3’ UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3’UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3’UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.
... The pathogenesis of sporadic ALS, which constitutes the majority of cases (around 90-95%), is less clear and likely involves a combination of genetic and environmental factors [3][4][5] . While specific gene mutations are not prevalent in sporadic ALS, genetic variants as risk factors can significantly contribute to disease susceptibility 6 . ...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.
... Therefore, attempts to elucidate disease mechanisms and pathogenic genetic variants are essential. Previous research has identified more than 30 genes associated with ALS, highlighting four genes SOD1, TARDBP (TDP-43), C90RF72 and FUS for harbouring pathogenic mutations which cause the greatest number of ALS cases [7][8][9][10]. Although these four genes have been identified as major ALS-associated genes, a 2017 meta-analysis study demonstrated that within European and Asian populations, these genes only contribute to 47.7% and 5.2% of familial and sporadic cases, respectively [11]. ...
Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs known as SINE-VNTR-Alu (SVA) demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), however the exact mechanism has yet to be identified. In this study we used whole genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Center ALS Consortium, to elucidate the influence of reference SVA elements on gene expression genome-wide within central nervous system (CNS) tissues. To investigate this, we applied matrix expression quantitative trait loci analysis and demonstrated that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position, and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative disease. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.
... 81 Genome-wide association studies (GWAS) conducted in large ALS cohorts have unveiled numerous ALS-modifying genes that can modulate the progression of the disease. 82 Currently, it remains uncertain whether these genetic modifiers may also contribute to determination of the tissue-specificity of TARDBP variants, such as G376V. ...
TDP-43-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their 5th-7th decade.
Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376 V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376 V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue.
The identification of individuals with TDP-43-related myopathy but not ALS implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype.
... Currently, mutations in more than 40 genes involved in various cellular processes have been linked to ALS, including proteostasis, ribostasis, DNA repair, cytoskeletal dynamics, and trafficking [36][37][38]. Among them, mutations in four genes, namely C9ORF72 (chromosome 9 open reading frame 72), SOD1 (Cu/n superoxide dismutase 1), TARDBP (transactive response DNA-binding protein 43 kDa), and FUS (fused in sarcoma), account for up to 70% of fALS. ...
... . Furthermore, an increasing number of studies report the presence of two or more mutations in different genes in ALS patients, suggesting the oligogenic inheritance of the disease in some cases [36]. In about 20% of fALS cases, the disease occurs due to mutations in the gene encoding the antioxidant enzyme SOD1, which in a healthy cell catalyzes the dismutation of superoxide anions into molecular oxygen and hydrogen peroxide [41,42]. ...
... Difficulties in developing effective genetic therapy are associated with the multifactorial nature of the disease [36]. The identification of novel mechanisms of ALS pathogenesis in recent years has resulted in growing numbers of proposed therapeutic approaches that are used to plan clinical trials. ...
Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing “quality control” and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.
... Around 10% of the ALS cases have a familial history (fALS), caused by mutations in one or several genes, mostly inherited in an autosomal dominant pattern (21). Of these, around 20% are associated with mutations in the Cu/Zn superoxide dismutase 1 (mSOD1) gene and approximately 40% in the chromosome 9 open reading frame 72 (C9orf72) gene, in Europe and the United States, and can drastically vary, notably in Asian patients (21)(22)(23). Experimental models for both mutations have been developed, namely the mSOD1 and the C9orf72 mice (24) that despite some limitations, recapitulate some of the main pathophysiological aspects of the disease. ...
Growing evidence demonstrates a continuous interaction between the immune system, the nerve and the muscle in neuromuscular disorders of different pathogenetic origins, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS), the focus of this review. Herein we highlight the complexity of the cellular and molecular interactions involving the immune system in neuromuscular disorders, as exemplified by DMD and ALS. We describe the distinct types of cell-mediated interactions, such as cytokine/chemokine production as well as cell-matrix and cell-cell interactions between T lymphocytes and other immune cells, which target cells of the muscular or nervous tissues. Most of these interactions occur independently of exogenous pathogens, through ligand-receptor binding and subsequent signal transduction cascades, at distinct levels of specificity. Although this issue reveals the complexity of the system, it can also be envisioned as a window of opportunity to design therapeutic strategies (including synthetic moieties, cell and gene therapy, as well as immunotherapy) by acting upon one or more targets. In this respect, we discuss ongoing clinical trials using VLA-4 inhibition in DMD, and in ALS, with a focus on regulatory T cells, both revealing promising results.
... This progressive neurodegenerative disease shares several factors with cancer, of which a relevant one is that the incidence increases with age. It shows a clinical progression with a complex pattern of inheritance, which rarely follows a rigorous Mendelian canon (24,25). Furthermore, similar to the pathological process in oncology, ALS involves a well-de ned cell population, i.e., the motor neurons. ...
Objective: Recent studies have suggested that the clinical onset of Amyotrophic Lateral Sclerosis (ALS) is the final expression of a multistep process. We evaluated the conformity of the hypothesis in a relatively small yet well-defined ALS population in the Province of Palermo, Sicily Island, almost entirely followed by the local tertiary ALS Clinical Center.
Methods: Incident data were extracted from the patients’ database of the ALS Center (years 2014-2020). We examined both sporadic and familial forms of the disease. To evaluate the multistep process in our population, we regressed the natural log of age-specific incidence against the natural log of age of the patients.
Results: We identified 175 ALS patients. We obtained a slope of 4.69 (r² = 0.986); the CI95% stands at 3.86-5.53 values, remaining relatively large due to the small sample share and with a p-value=0.00038. The slope estimate was consistent with a 6-step process.
Conclusions. In the ALS population of the Province of Palermo, Sicily, the multistep analysis confirms a process consistent with a 6-step model. This data, obtained in a relatively homogeneous population, further highlights the probability of strict interaction between environmental and genetic variables in the disease. Our data offer insights into the complexity of the mechanisms involved in the pathogenesis of the disease, particularly during its asymptomatic phase. This study supports the hypothesis that a single therapeutic silver bullet would probably be insufficient to arrest or slow the disease’s progression.
