<b>Background:</b> Pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases, and can be associated with risks for ALS only, or risks for other neurodegenerative diseases (eg. frontotemporal dementia).
Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS).
In this study, we have characterized both protein and RNA TDP-43 interactors from neuropathologically normal (control) and ALS-affected ventral lumbar spinal cord, including sporadic ALS (sALS) and familial cases harboring either a A4T mutant SOD1 or a 3' UTR *c.41G>A mutant FUS/TLS or expressing pathological c9orf72 expanded repeats.
The structural instability of SOD1 and the detection of SOD1-positive inclusions in familial-ALS patients supports a potential causal role for misfolded and/or aggregated SOD1 in ALS pathology.
Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated.
Mutations in the Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) gene underlie 14-23 % of familial and 1-7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord.
Most cases of ALS are sporadic, but 10% are familial and mutations affecting the copper (Cu)-dependent antioxidant Cu/Zn-superoxide dismutase (SOD1) are the most common familial cause.
Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS.
Hexanucleotide repeat expansion in the bi-directionally transcribed C9orf72 gene is the most frequent cause of familialALS and frontotemporal dementia (FTD).Kramer et al.
Aggregation of copper-zinc superoxide dismutase (SOD1) is a defining feature of familialALS caused by inherited mutations in the sod1 gene, and misfolded and aggregated forms of wild-type SOD1 are found in both sporadic and familialALS cases.
Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey.
In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases.
Although most cases of ALS are sporadic, about 5-10% of cases are familial (FALS) with approximately 20% of FALS caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene.
About 10% of all ALS cases are familial (fALS), among which 15-20% are linked to Cu/Zn superoxide dismutase (SOD1) mutations, usually inherited in an autosomal dominant manner.
Previously, we screened mutations in 5 ALS genes including SOD1 and FUS in 9 fALS and 249 sALS patients and found a total of 15 patients with either SOD1 (7 fALS and 3 sALS) or FUS (1 fALS and 4 sALS) mutations.
NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice.
While most cases of ALS are sporadic, 10% are familial (FALS) with 20% of FALS caused by a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1).