Neurodegeneration and inflammation in a novel spinocerebellar ataxia 13 preclinical model

Abstract Neuroinflammation is a critical pathological feature underlying neurodegenerative diseases. Spinocerebellar ataxia 13 (SCA13) is a heterogeneous ataxia with several allelic variations of differing phenotypes. All are neurodegenerative and currently without effective treatment. Our prior work identified human KCNC3 gene mutations as causative for SCA13, with the R423H allelic isoform specifically driving early-onset neurodegeneration. The precise nature of the inflammatory response and its link to neurodegeneration in SCA13 remains elusive. To address this, we engineered a single Kcnc3 R424H mutation (analogous to the human SCA13 KCNC3 R423H allele) into mice using CRISPR/Cas9. We performed thorough phenotypic analyses including motor function (gait, tremor, coordination, balance) and brain segmental /cerebellar volume at multiple timepoints. We then investigated both neurodegenerative Purkinje cell loss and inflammatory responses within the cerebellum (astroglia and microglia) and systemically (plasma cytokine levels). At 3 and 6 months of age, the R424H mice displayed profound neurological motor dysfunction, including high-frequency tremor, aberrant gait, and a decreased latency to fall. Electrophysiology revealed dysregulated spontaneous firing in Purkinje cells. Pathological examination confirmed progressive Purkinje cell degeneration and cerebellar atrophy. Critically, we observed a pronounced activation of microglia and astrocytes within the cerebella of R424H mice. Pearson correlation analyses highlighted a strong inverse correlation between the number of surviving Purkinje cells and markers of inflammatory activation. In conclusion, our transgenic R424H mice establish a novel model of brain hypoplasia and neurodegeneration caused by dysfunction of a voltage-gated potassium channel mimicking SCA13 R423H , exhibiting significant motor deficits, prominent Purkinje cell loss, cerebellar inflammation, and atrophy. This study strongly suggests that the aberrant activation of inflammatory immune cells, notably astroglia and microglia, is associated with Purkinje cell demise in the cerebellum. We propose that this observed neuroinflammation may play a significant and potentially aggressive role in driving the progression of neurodegeneration in SCA13.