Bartelt Luke C, Switonski Pawel M, Adamek Grażyna, Carvalho Juliana, Duvick Lisa A, Jarrah Sabrina I, McLoughlin Hayley S, Scoles Daniel R, Pulst Stefan M, Orr Harry T, Hull Court, Lowe Craig B, La Spada Albert R
University Program in Genetics & Genomics, Duke University Medical Center, Durham, NC 27710, USA.
Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine; Irvine, CA 92697, USA.
bioRxiv. 2023 May 11:2023.03.19.533345. doi: 10.1101/2023.03.19.533345.
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological.
7型脊髓小脑共济失调（SCA7）是一种由CAG-聚谷氨酰胺重复序列扩增引起的遗传性神经退行性疾病。随着疾病进展，SCA7患者的浦肯野细胞（PC）神经元显著丧失；然而，PC细胞很罕见，难以进行特征描述。我们开发了一种PC细胞核富集方案，并将其应用于SCA7基因敲入小鼠模型的单核RNA测序。我们的结果将先前的观察结果统一为细胞身份丧失的核心机制，这一机制影响神经胶质细胞和PC细胞，导致抑制性突触积累和PC细胞放电改变。斑马蛋白II亚型失调是PC细胞中的主要信号，导致SCA7小鼠在出现运动症状时斑马蛋白II条纹完全消失。我们表明，这种斑马蛋白II亚型降解在多聚谷氨酰胺共济失调小鼠模型和SCA7患者中都存在。据推测，PC细胞亚型组织对小脑功能至关重要，我们的结果表明斑马蛋白II矢状旁条纹的破坏是病理性的。
