| First Author | Luttik K | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 34 | Pages | e2208513119 |
| PubMed ID | 35969780 | Mgi Jnum | J:340363 |
| Mgi Id | MGI:7437419 | Doi | 10.1073/pnas.2208513119 |
| Citation | Luttik K, et al. (2022) Differential effects of Wnt-beta-catenin signaling in Purkinje cells and Bergmann glia in spinocerebellar ataxia type 1. Proc Natl Acad Sci U S A 119(34):e2208513119 |
| abstractText | Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease characterized by progressive ataxia and degeneration of specific neuronal populations, including Purkinje cells (PCs) in the cerebellum. Previous studies have demonstrated a critical role for various evolutionarily conserved signaling pathways in cerebellar patterning, such as the Wnt-beta-catenin pathway; however, the roles of these pathways in adult cerebellar function and cerebellar neurodegeneration are largely unknown. In this study, we found that Wnt-beta-catenin signaling activity was progressively enhanced in multiple cell types in the adult SCA1 mouse cerebellum, and that activation of this signaling occurs in an ataxin-1 polyglutamine (polyQ) expansion-dependent manner. Genetic manipulation of the Wnt-beta-catenin signaling pathway in specific cerebellar cell populations revealed that activation of Wnt-beta-catenin signaling in PCs alone was not sufficient to induce SCA1-like phenotypes, while its activation in astrocytes, including Bergmann glia (BG), resulted in gliosis and disrupted BG localization, which was replicated in SCA1 mouse models. Our studies identify a mechanism in which polyQ-expanded ataxin-1 positively regulates Wnt-beta-catenin signaling and demonstrate that different cell types have distinct responses to the enhanced Wnt-beta-catenin signaling in the SCA1 cerebellum, underscoring an important role of BG in SCA1 pathogenesis. |
