Widner James, Faust Phyllis L, Louis Elan D, Fujita Hirofumi
Movement Disorder Section, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75235.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032.
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2502024122. doi: 10.1073/pnas.2502024122. Epub 2025 Jun 30.
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 postmortem 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, and 2) provide evidence of region-specific PC populations in the human cerebellum and offer insight into how different PC subpopulations may contribute to the pathophysiology of cerebellar degeneration.
小脑皮质被组织成不同的区域，这些区域由分子特征不同的浦肯野细胞（PCs）构成，浦肯野细胞是皮质唯一的输出神经元。虽然动物模型研究表明PC亚型对疾病的易感性不同，但我们对人类PC亚型及其易感性的了解仍然有限。在这里，我们证明，专门负责运动功能与认知功能的人类小脑区域（小叶HV与 Crus I）包含具有特定分子和解剖特征的不同PC群体，这些群体在特发性震颤（ET）（一种小脑退行性疾病）中表现出选择性易损性。使用已知的PC亚型标志物神经丝重链（NEFH），我们发现，在健康对照的尸检样本中，运动小叶HV包含高表达NEFH的PCs，而认知小叶Crus I包含低表达NEFH的PCs。在同一小脑中，小叶HV中的PC轴突比Crus I中的粗2.2倍。在不同小叶中，轴突直径与NEFH表达呈正相关。在ET小脑中，我们发现运动小叶特异性的PC轴突病变，小叶HV中轴突直径减少了1.5倍，轴突变异性增加，而Crus I轴突未受影响。ET中的震颤严重程度和持续时间与小叶HV中PC轴突直径变异性选择性相关。鉴于轴突直径是神经信号传导能力的主要决定因素，我们的结果1）表明ET中发生了小脑皮质核信号传导中断，2）提供了人类小脑中区域特异性PC群体的证据，并深入了解了不同PC亚群如何可能导致小脑变性的病理生理学。
