Repeat associated neurodegeneration in CANVAS

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Abstract: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive and recessively inherited ataxia characterized by vestibular, cerebellar, and somatosensory impairments and cerebellar degeneration that results in significant morbidity and early mortality. CANVAS is caused by a biallelic, non-reference, pentameric AAGGG repeat expansion within the second intron of replication factor complex subunit 1 (RFC1) gene in both familial and sporadic CANVAS, as well as a significant fraction of all late-onset degenerative ataxias and sensory neuronopathies. Controls possess an average of 11 AAAAG repeats at this locus, which is replaced with between 400-2000 AAGGG repeats in CANVAS patients. The mechanism(s) by which this repeat expansion causes neurodegeneration are unknown. While CANVAS exhibits a recessive pattern of inheritance, studies to date suggest that RFC1 expression is not impacted by the repeat expansions. The expansion has the potential to be pathogenic within two different strand-specific contexts. On the sense strand, the (AAGGG)n repeat sits within the poly(A) tail of an AluSx3 transposable element, while the antisense strand (CCCTT)n repeat sits within the large second intronic region of RFC1. The goal of this proposal is to define the mechanisms by which these repeat elements contribute to neurodegeneration in CANVAS. To accomplish this, we will use a combination of patient-derived iPSC models alongside studies using repeat-expressing reporters to investigate the expanded repeat within both its endogenous context as well as within easily manipulable assay systems that will allow us to define the potential of these repeat elements to elicit toxicity directly. Taken together, these studies will provide critical information needed to define the proximal mechanism(s) and pathways that underlie neuronal toxicity and neurodegeneration within CANVAS – a critical first step required for development of disease relevant therapeutics.