Open AccessmiRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3
Author(s) -
Rui Jorge Nobre,
Diana Lobo,
Carina Henriques,
Sónia Duarte,
Sara Lopes,
Ana C Silva,
Miguel M Lopes,
Fanny Mariet,
Lukas Schwarz,
M. S. Baatje,
Valérie Ferreira,
Astrid Vallès,
Luís Pereira de Almeida,
Melvin M. Evers,
Lodewijk J.A. Toonen
Publication year - 2022
Publication title -
nucleic acid therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.255
H-Index - 67
eISSN - 2159-3345
pISSN - 2159-3337
DOI - 10.1089/nat.2021.0020
Subject(s) - gene knockdown , spinocerebellar ataxia , biology , ataxia , machado–joseph disease , microbiology and biotechnology , neuroscience , genetics , gene
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by the expansion of a CAG repeat in the ATXN3 gene. This mutation leads to a toxic gain of function of the ataxin-3 protein, resulting in neuronal dysfunction and atrophy of specific brain regions over time. As ataxin-3 is a dispensable protein in rodents, ataxin-3 knockdown by gene therapy may be a powerful approach for the treatment of SCA3. In this study, we tested the feasibility of an adeno-associated viral (AAV) vector carrying a previously described artificial microRNA against ATXN3 in a striatal mouse model of SCA3. Striatal injection of the AAV resulted in good distribution throughout the striatum, with strong dose-dependent ataxin-3 knockdown. The hallmark intracellular ataxin-3 inclusions were almost completely alleviated by the microRNA-induced ATXN3 knockdown. In addition, the striatal lesion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) in the SCA3 mice was rescued by ATXN3 knockdown, indicating functional rescue of neuronal signaling and health upon AAV treatment. Together, these data suggest that microRNA-induced ataxin-3 knockdown is a promising therapeutic strategy in the treatment of SCA3.