Rad23b exacerbates pathological aggregates through disrupting proteasome functions in Spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally, caused by expanded CAG repeats in the ATXN3 gene and consequent pathogenic accumulation of mutant ATXN3 (mATXN3) aggregates. The formation of these aggregates perturbs neuronal functions and leads to progressive neurodegeneration, yet the molecular mechanisms controlling mATXN3 proteostasis remain incompletely understood. Here, we identify RAD23 homolog B (Rad23b), a ubiquitin-binding shuttle factor, as a potential regulator of mATXN3 aggregates and toxicity upon high throughput proteomic analysis. Functional assays reveal that Rad23b overexpression enhances, while Rad23b knockdown or knockout reduces, mATXN3 aggregates and neuronal cell death. Mechanistically, Rad23b directly interacts with mATXN3, promotes its ubiquitination, and facilitates its delivery to the proteasome. Paradoxically, Rad23b disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Immunohistochemical analysis in SCA3 transgenic mice confirms colocalization of Rad23b with mATXN3 aggregates in cerebellar neurons. These findings highlight Rad23b as a crucial modulator of mATXN3 proteostasis, and imply Rad23b as a potential therapeutic target in SCA3.