Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

Abstract

Objective: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion.Methods: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS).Results: We found a significant association with intermediate repeat size ($29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls.Conclusions: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS.Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered part of a spectrum of neurologic diseases because they share pathologic hallmarks, consisting of TAR DNA-binding protein 43 (TDP-43) pathology, and a similar genetic background, including C9orf72 expansion. On the other hand, FTD shares a prominent frontal cognitive syndrome and parkinsonism signs with progressive supranuclear palsy (PSP). Spinocerebellar ataxia type 2 (SCA2), characterized by cerebellar ataxia, parkinsonism, and mild dementia, is caused by an expanded CAG trinucleotide repeat encoding for a polyglutamine (polyQ) tract in ataxin-2 protein (ATXN2; OMIM: *601517). A link between SCA2 and ALS was established in 2010, when ATXN2 intermediate-length expansions were found to be significantly associated with ALS and it was shown that ATXN2 protein modifies TDP-43 toxicity.1 In this study, we analyzed the size of ATXN2 repeats in a large French cohort of 1,624 patients with ALS, FTD, FTD-ALS, and PSP to evaluate the exact contribution of the ATXN2 repeat size to

Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

“…The polyQ-expansion of ATXN2 leads to a process of protein insolubility and aggregate formation with insidious toxicity throughout the nervous system, depending on the expansion size and polygenic interactions, possibly also on CAA-interruptions within the CAG-repeat. Neurodegenerative processes known as Spino-cerebellar Ataxia type 2 (SCA2), the motor neuron degeneration Amyotrophic Lateral Sclerosis (ALS13), Frontotemporal dementia, Supranuclear palsy, or Levodopa-responsive Parkinsonism can be triggered by this mechanism (32)(33)(34)(35)(36)(37)(38)(39). In Drosophila melanogaster flies, the Ataxin-2 ortholog dATX2 was shown to act as a generic modifier gene that affects multiple if not all neurodegenerative disorders (40).…”

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

“…A large cohort study on 1255 affected patients allowed an assessment to be made of the influence on the age at onset of the length of the normal allele in trans (SCA1, 6, 7) and of other (CAG)n-containing genes [57]. Furthermore, intermediate-size CAG repeats in ATXN2 were recently shown to be a risk factor in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia with ALS ([29 repeats [58]), and possibly in Parkinson's disease ([24 repeats [59]). Conventional mutations can also act as modifiers.…”

Emerging role of RNA•DNA hybrids inC9orf72-linked neurodegeneration

“…Recently, the intermediate-length repeat in ataxin-2 was observed to be a potential disease modifier in C9orf72 expansion carriers and there is a co-occurrence of the 2 expansion mutations in ALS/FTD patients. 96,97 Human ataxin-2 has been implicated in multiple RNA-processing functions; however, its potential function in modulating R-loops, if confirmed, could provide a mechanistic link among these neurodegenerative diseases.…”