Purkinje cell development and degeneration in the spastic Han-Wistar rat model of ataxia

Abstract

Abstract Hereditary ataxia is a neurodegenerative disorder notable for its early onset, with symptoms appearing in patients as young as two years old. Although affected individuals exhibit severe motor deficits and early mortality rates, the timeline of Purkinje cell loss remains unclear. To address this gap, we used the spastic Han-Wistar rat model, which harbors an unknown homozygous recessive variant that causes Purkinje cell loss. Here, we determined the onset and temporal progression of Purkinje neuronal loss in the spastic Han-Wistar model. To achieve this, we employed immunohistochemistry, Hematoxylin and Eosin histology, and neuronal density quantification. Behavioral testing demonstrated early-onset, progressive motor impairment in mutant rats, with motor deficits emerging around P45, following Purkinje cell loss detectable as early as P15. Additionally, guided by pedigree analysis indicating autosomal recessive inheritance for this ataxia, we performed whole-genome shotgun sequencing of a parent-offspring trio to identify amino acid-changing mutations consistent with this pattern. Sanger sequencing excluded Sbf2 as a causal variant, and whole-genome sequencing identified 273 candidate genes consistent with autosomal recessive inheritance. Together, our findings provide new insights into the onset and genetic complexity of ataxia, refining the value of the spastic Han-Wistar rat as a model for investigating mechanisms underlying hereditary ataxia.