The pathobiology of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) : a proteinopathy?

Abstract

Ample neurological disorders are associated with expanded repeats in various genes' intron, exon, or regulatory regions (Loureiro et al., 2022). Guanine-rich pentameric and hexameric repeats are closely linked with spinocerebellar ataxia type 31 (SCA31), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (C9orf72), and Fragile X-associated tremor/ataxia syndrome (FXTAS) (Currò et al., 2021; Loureiro et al., 2022; Montaut et al., 2021). They are reported to form highly stable secondary structures, and G quadruplex conformations in-vitro and in-vivo. CANVAS, a slowly progressive neurodegenerative disorder, is also associated with the biallelic expansion of (AAGGG) pathogenic repeat in its second intron of the RFC1 gene (Cortese et al., 2019). Though these guanine-rich pathogenic repeats in other neurological diseases are associated with Loss of Function, RNA gain of function (RNA foci and protein sequestration), and/or protein gain of function, there is no conclusive pathological mechanism associated with CANVAS (Loureiro et al., 2022).