AAGGG repeat expansions trigger <i>RFC1</i> -independent synaptic dysregulation in human CANVAS neurons-Reference-Cited by-同舟云学术

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

Published:2024-09-06 Issue:36 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Maltby Connor J.¹^ORCID,Krans Amy¹²,Grudzien Samantha J.¹³⁴^ORCID,Palacios Yomira¹⁵^ORCID,Muiños Jessica¹⁶^ORCID,Suárez Andrea¹⁵,Asher Melissa¹^ORCID,Willey Sydney¹³^ORCID,Van Deynze Kinsey⁴^ORCID,Mumm Camille⁴⁷^ORCID,Boyle Alan P.⁴^ORCID,Cortese Andrea⁸⁹,Ndayisaba Alain¹⁰^ORCID,Khurana Vikram¹⁰¹¹,Barmada Sami J.¹^ORCID,Dijkstra Anke A.¹²¹³^ORCID,Todd Peter K.¹²^ORCID

Affiliation:

1. Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

2. Ann Arbor Veterans Administration Healthcare, Ann Arbor, MI, USA.

3. Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.

4. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

5. Postbaccalaureate Research Education Program, University of Michigan, Ann Arbor, MI, USA.

6. UM SMART Undergraduate Summer Program, University of Michigan, Ann Arbor, MI, USA.

7. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.

8. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.

9. Department of Brain and Behaviour Sciences, University of Pavia, Pavia 27100, Italy.

10. Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

11. Harvard Stem Cell Institute, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

12. Department of Pathology, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Netherlands.

13. Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adn2321

Reference88 articles.

1. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects

2. Proposed diagnostic criteria for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS)

3. CANVAS with cerebellar/sensory/vestibular dysfunction from RFC1 intronic pentanucleotide expansion

4. The Pathology of the Vestibular System in CANVAS

5. Clinico-pathological correlates in cerebellar ataxia with neuronopathy and vestibular areflexia syndrome (CANVAS)