Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line

Stem Cell Research
Lauren R MooreH L Paulson

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. In addition, SCA3-hESCs exhibit nuclear accumulation of mutant ATXN3 and form p62-positive aggresomes. Finally, antisense oligonucleotide-mediated reduction of ATXN3 markedly suppressed aggresome formation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3.

Citations

Oct 10, 2020·Annual Review of Pharmacology and Toxicology·C Frank BennettDon W Cleveland
May 26, 2021·Stem Cell Reviews and Reports·Marina P HommersomHans van Bokhoven
Jun 24, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Nan ZhangTetsuo Ashizawa
Nov 26, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yalan ZhangLeonard K Kaczmarek

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