Decreasing Mutant ATXN1 Nuclear Localization Improves a Spectrum of SCA1-Like Phenotypes and Brain Region Transcriptomic Profiles

Authors

Hillary P Handler
Lisa Duvick
Jason S Mitchell
Marija Cvetanovic
Molly Reighard
Alyssa Soles
Kathleen B Mather
Orion Rainwater
Shannah Serres
Tessa Nichols-Meade
Stephanie L Coffin
Yun You
Brian L Ruis
Brennon O'Callaghan
Christine Henzler
Huda Y Zoghbi
Harry T Orr

Publication Date

2-15-2023

Journal

Neuron

DOI

10.1016/j.neuron.2022.11.017

PMID

36577403

PMCID

PMC9957934

PubMedCentral® Posted Date

2-15-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Mice, Ataxin-1, Brain, Cerebellum, Disease Models, Animal, Mice, Transgenic, Nerve Tissue Proteins, Phenotype, Protein Transport, Purkinje Cells, Spinocerebellar Ataxias, Transcriptome, Spinocerebellar ataxia type 1, SCA1, neurodegeneration, nuclear localization

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates that proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1