Mutant PolyQ Ataxin-7 Induces Premature Senescence in Human Müller Glial Cells via Genomic Instability

Spinocerebellar ataxia type 7 (SCA7) is a severe hereditary neurodegenerative disorder primarily affecting the cerebellum and retina. It stems from an expanded polyQ tract in the ATXN7 gene, leading to protein misfolding and neuronal/glial degeneration. A critical gap in understanding SCA7 pathogenesis is the role of altered DNA damage response (DDR), which can trigger cellular senescence. Senescent cells have been observed in SCA7 mouse models, suggesting their contribution to disease progression. This study investigates how mutant ataxin-7 drives genomic instability and premature senescence in glial cells, a mechanism potentially underlying glial pathogenesis in SCA7.

Researchers utilized a human Müller glial cell model, MIO-M1, engineered to express either normal (10Q) or expanded (64Q) ataxin-7. The study aimed to determine if the mutant protein induces genomic instability and subsequent senescence. They assessed markers of genomic instability, including nuclear lamina organization, γH2AX foci (a DDR marker), micronuclei formation, and telomere shortening. Senescence hallmarks were evaluated by examining heterochromatin loss, senescence-associated β-galactosidase activity, and expression levels of p21 and p53. Nucleolar morphology was also analyzed to identify specific senescence-related changes.

Expression of expanded 64Q polyQ ataxin-7 significantly disrupted nuclear lamina organization in MIO-M1 cells. This disruption was accompanied by clear signs of genomic instability, including the presence of γH2AX foci, increased micronuclei formation, and telomere shortening. These findings collectively indicate that mutant ataxin-7 directly elicits genomic instability within these glial cells. Furthermore, the 64Q cells exhibited several key hallmarks of cellular senescence:

They displayed pronounced heterochromatin loss and a notable increase in senescence-associated β-galactosidase activity, a canonical marker of senescent cells. However, unlike typical senescence, there was no observed increase in p21 or p53 expression. Interestingly, instead of the characteristic enlargement of nucleoli often seen in senescence, the 64Q cells showed nucleolar disaggregation. These results strongly suggest that polyQ ataxin-7 expression induces a distinct senescence-like phenotype driven by nuclear architectural disruption and genomic instability.