A GGGGCC hexanucleotide repeat expansion in intron 1 of chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
Mutations in the gene encoding Cu/Zn Superoxide Dismutase 1 (SOD1) protein are contemplated to be a protruding reason for Amyotrophic lateral sclerosis (ALS), which leads towards protein aggregation, misfolding and destabilization.
The combined proteomic analysis allowed the detection of regulated proteins linked to ALS pathogenesis (RNA-binding protein FUS, superoxide dismutase Cu-Zn and neurofilaments light polypeptide) alongside newly identified candidate biomarkers (myosin-9, fructose-bisphosphate aldolase and plectin).
Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord.
SOD1 activity threshold and TOR signalling modulate VAP(P58S) aggregation via reactive oxygen species-induced proteasomal degradation in a <i>Drosophila</i> model of amyotrophic lateral sclerosis.
Data from clinical studies show that multiple genetic mutations linked to ALS (eg, mutations in SOD1, TARDBP, and C9orf72) enhance this neuroinflammation, which provides compelling evidence for immune dysregulation in the pathogenesis of ALS.
We propose that translational incorporation of BMAA into SOD1 is directly responsible for its toxicity in neurodegeneration, and BMAA modification of SOD1 may serve as a biomarker of ALS.
An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)<sub>30+</sub>) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9<sup>+</sup>).
A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia.
As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs.
Our results highlight the importance of including Africans in genetic studies aimed at unravelling the genomic architecture in ALS and suggest pathogenetic mechanisms other than the C9orf72 expansion in black Africans with ALS.
Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).
Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95).
Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs).
These novel findings for LCN-SOD1 mice are congruent with reported dysphagia and associated tongue atrophy and hypoglossal nucleus pathology in human ALS patients, thus highlighting the translational potential of this mouse model in ALS research.