Nuclear Lamina Dysfunction and DNA Damage as Drivers of Premature Senescence in a Human Müller Glial Cell Model of Spinocerebellar Ataxia Type 7

Spinocerebellar ataxia type 7 (SCA7) is a hereditary disorder characterized by degeneration of the cerebellum and retina. SCA7 is caused by the expansion of a polyQ tract in the ATXN7 gene, leading to protein misfolding, transcriptional dysregulation, and neuronal/glial degeneration. Recently, altered DNA damage response (DDR) was revealed in SCA7, which may contribute to disease pathogenesis. Impaired DDR causes DNA damage, which in turn triggers cellular senescence. Consistently, senescent cells were identified in the cerebellum Purkinje layer of an SCA7 mouse model. In this study a Müller glial model (MIO-M1) expressing normal (10Q) or expanded (64Q) ataxin-7 was utilized to ascertain whether mutant protein induces genomic instability and consequently the emergence of senescence. PolyQ ataxin-7 elicits nuclear lamina disorganization, γH2AX foci (DDR marker), micronuclei and telomere shortening, which indicate genomic instability. Furthermore, 64Q cells expressing polyQ ataxin-7 exhibited senescence hallmarks, including heterochromatin loss and increased senescence-associated β-galactosidase activity, but not p21 nor p53 expression. Instead of the senescence-associated enlargement of nucleoli, these cells exhibited nucleolar disaggregation. Together, these findings indicate that the expression of polyQ ataxin-7 disrupts the nuclear architecture, thereby inducing genomic instability. This, in turn, results in a senescence-like phenotype, a phenomenon that may contribute to glial pathogenesis.