biostudies-literatureUnknownMaltby CJBLRD VANICHD NIH HHSNINDS NIH HHSCerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (<i>RFC1</i>). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) 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 selectivebioRxiv : the preprint server for biology2023.12.13.571345https://www.ebi.ac.uk/biostudies/studies/S-EPMC10760133biostudies-literatureAAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons.PMC10760133I01 BX004842R01 NS086810R01 NS113943P50 HD104463R01 NS097542R21 NS129096R56 NS128110Grudzien SJPalacios YKhurana VMaltby CJTodd PKKrans AMuinos JAsher MBarmada SJDijkstra AASuarez AfalseAAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons.Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (<i>RFC1</i>). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) 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 selective2023-01-01T00:00:00Z2023 Dec2025-08-31T03:11:06.889Z2025-08-31T03:05:16.211ZS-EPMC107601333816817110.1101/2023.12.13.571345