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AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248345 | GEO | 2024/09/01

REPOSITORIES: GEO

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AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS neurons.

Project description:Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited neurodegenerative disorder caused by intronic biallelic, nonreference CCCTT/AAGGG repeat expansions within RFC1. To investigate how these repeats cause disease, we generated patient induced pluripotent stem cell-derived neurons (iNeurons). CCCTT/AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway function. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins. However, these proteins and repeat RNA foci were not detected in iNeurons, and overexpression of these repeats failed to induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded AAGGG allele. These deficits were neither replicated by RFC1 knockdown in control iNeurons nor rescued by RFC1 reprovision in CANVAS iNeurons. These findings support a repeat-dependent but RFC1 protein-independent cause of neuronal dysfunction in CANVAS, with implications for therapeutic development in this currently untreatable condition.

| S-EPMC11373605 | biostudies-literature

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Addition]

Project description:Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by a biallelic, non-reference pentameric CCCTT(AAGGG) repeat expansion within the second intron of replication factor complex subunit 1 (RFC1). While rare compound heterozygous CANVAS cases harbor RFC1 loss-of-function mutations alongside monoallelic repeat-expansions, RFC1 expression is maintained at normal levels in the presence of biallelic expanded repeats. To investigate how these pentameric repeats cause disease, we generated CANVAS patient iPSC derived neurons and utilized calcium imaging and transcriptomic analysis to define repeat elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. Importantly, these deficits were not replicated by knockdown of RFC1 in control neurons and showed incomplete or no rescue upon over-expression of RFC1. These findings support a repeat-dependent and RFC1-independent mechanism as the underlying cause of neurodegeneration in CANVAS, with important implications for therapeutic development in this currently untreatable condition.

2024-09-01 | GSE248344 | GEO

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [RFC1_Knockdown]

2024-09-01 | GSE248343 | GEO

AAGGG repeat expansions trigger repeat-dependent synaptic dysregulation in human CANVAS Neurons [CANVAS_Control_Isogenic]

2024-09-01 | GSE248342 | GEO