Axonal pathology differentially affects human Purkinje cell subtypes in the essential tremor cerebellum

The cerebellar cortex is organized into discrete regions populated by molecularly distinct Purkinje cells (PCs), the sole cortical output neurons. While studies in animal models have shown that PC subtypes differ in their vulnerability to disease, our understanding of human PC subtype and vulnerability remains limited. Here, we demonstrate that human cerebellar regions specialized for motor vs cognitive functions (lobule HV vs Crus I) contain distinct PC populations characterized by specific molecular and anatomical features, which show selective vulnerability in essential tremor (ET), a cerebellar degenerative disorder. Using a known PC subtype marker, neurofilament heavy chain (NEFH), we found that motor lobule HV contains PCs with high NEFH expression, while cognitive lobule Crus I contains PCs with low NEFH expression in post-mortem samples from healthy controls. In the same cerebella, PC axons in lobule HV were 2.2-fold thicker than those in Crus I. Across lobules, axon caliber positively correlated with NEFH expression. In ET cerebella, we identified motor lobule-specific PC axon pathology with a 1.5-fold reduction in caliber and increased axon variability in lobule HV, while Crus I axons were unaffected. Tremor severity and duration in ET correlated with axon diameter variability selectively in lobule HV PCs. Given that axonal caliber is a major determinant of neural signaling capacity, our results (1) suggest that disrupted cerebellar corticonuclear signaling is occurring in ET, (2) provide evidence of region-specific PC subtypes in the human cerebellum and offer insight into how selective PC vulnerability may contribute to the pathophysiology of cerebellar degeneration. Significance StatementThe cerebellar cortex has a uniform laminar architecture but contains heterogeneous cell types. Purkinje cells (PCs), the sole output cells of the cerebellar cortex, include subtypes whose lobular distribution is thought to underlie functional segmentation and patterned degeneration of the cerebellum in animal models. However, human PC subtypes and their disease vulnerability remain unknown. Here, we establish the existence of human PC subtypes that appear conserved across mammalian species using both marker expression and axonal thickness. Consistent with its phenotype, we demonstrate differential PC vulnerability to degeneration in essential tremor cerebella, where motor function- mediating PC subtypes display significant axonal thinning, while axons of cognitive function-mediating PC subtypes are spared. These findings advance Purkinje cell type- oriented research in cerebellar disorders.