Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice

Abnormal expansions of the CAG trinucleotide repeat within specific gene exons give rise to polyglutamine (polyQ) diseases, a family of inherited disorders characterized by late-onset neurodegeneration. Recently, a new type of polyQ disease was identified and named spinocerebellar ataxia 51 (SCA51). SCA51 is caused by polyQ expansion in THAP domain containing 11 (THAP11), an essential transcription factor for brain development. The pathogenesis of SCA51, particularly how mutant THAP11 with polyQ expansion contributes to neuropathology, remains elusive. Our study of mouse and monkey brains revealed that THAP11 expression is subject to developmental regulation, showing enrichment in the cerebellum. However, knocking down endogenous THAP11 in adult mice did not affect neuronal survival. In contrast, expressing mutant THAP11 with polyQ expansion led to pronounced protein aggregation, cerebellar neurodegeneration, and motor deficits, indicating that gain-of-function mechanisms are central to SCA51 pathogenesis. We discovered activated microglia expressing triggering receptor expressed on myeloid cells 2 (TREM2) in the cerebellum of a newly developed SCA51 knockin mouse model. Mechanistically, mutant THAP11 enhanced the transcription of TREM2, leading to its upregulation. The loss of TREM2 or depletion of microglia mitigated neurodegeneration induced by mutant THAP11. Our study offers the first mechanistic insights to our knowledge into the pathogenesis of SCA51, highlighting the role of TREM2-mediated microglial activation in SCA51 neuropathology.