Differential impact of mutant Ataxin-3 in hindbrain regions: further evidence of white matter loss as a core pathological feature.

Spinocerebellar ataxia type 3 (SCA3) is a devastating neurodegenerative disorder that belongs to the family of polyglutamine disorders. Although the CAG repeat expansion underlying SCA3 was discovered 30 years ago, there is still no cure or treatment able to delay its progression. One of the reasons for this lag may be attributed to the phenotypic and neuropathological heterogeneity among individuals. To overcome this gap, we aimed to delve into the specific contributions of hindbrain regions that have been consistently reported to be the most degenerated in SCA3 patients, the cerebellar cortex, namely lobules IV-V, VIII and IX, deep cerebellar nuclei and the pons. For this purpose, we used lentiviral vectors to deliver the SCA3-causing gene, mutant Ataxin-3, to these specific regions in mice. We observed that the overexpression of mutant Ataxin-3 in different hindbrain regions led to the formation of Ataxin-3 aggregates in neuronal cells and mild motor impairments. Neurons in the pons were more vulnerable to mutant Ataxin-3 overexpression than in the cerebellum. There was also an increase in astrocytes and microglia recruitment that may explain myelin damage and, consequently, white matter loss in the cerebellum. Indeed, cerebellar white matter loss was the most broadly observed pathological feature upon overexpression of mutant Ataxin-3 in different regions of the hindbrain. In conclusion, we confirm that cerebellar white matter changes are a consistent feature of SCA3 neuropathology, and demonstrate that the region-specific lentiviral models offer a valuable platform to study early, selective pathological mechanisms and support future therapeutic testing.