Expanded ATXN3 CAG Repeat is Stable in Human Purkinje Cells

Background Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by an abnormally long polyglutamine‐encoding CAG repeat in the ATXN3 gene. Objectives We aimed to determine whether somatic expansion of the mutant ATXN3 ( mATXN3 ) CAG repeat is present in the output cell of the cerebellar cortex, the Purkinje cell (PC), in individuals affected with SCA3. Methods We combined sorting of cell nuclei from post‐mortem brain tissue, transcriptome analysis‐based confirmation of sample purity, and high‐depth sequencing of ATXN3 exon 10 amplicons to analyze the stability of mATXN3 CAG repeat in PCs in individuals with SCA3. Results We demonstrated that the expansion of mATXN3 CAG repeat in PCs is minimal, comparable with cerebellar granule neurons, and the repeat is more stable in PCs compared with striatal medium spiny neurons. Conclusion The modest somatic expansion of the mATXN3 CAG repeat observed in PCs is likely not responsible for their loss in individuals with SCA3.