Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

中文翻译：

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Capicua 表达的改变通过 1 型脊髓小脑共济失调中离子通道基因失调驱动区域浦肯野神经元脆弱性。


神经退行性疾病中的选择性神经元脆弱性尚不清楚。使用 1 型脊髓小脑共济失调 (SCA1) 的 ATXN1[82Q] 模型，我们探索了这样的假设：浦肯野神经元变性的区域差异可以为选择性脆弱性提供新的见解。研究发现，小脑前部的 ATXN1[82Q] 浦肯野神经元比结节区的浦肯野神经元退化得更早，这种早期退化与离子通道转录本的选择性失调和浦肯野神经元尖峰的改变有关。为了了解通道转录本选择性失调的基础，我们发现小脑前部浦肯野神经元中 ATXN1 辅助抑制因子 Capicua (Cic) 的表达略有增加。重要的是，破坏 ATXN1 和 Cic 之间的关联可以挽救这些离子通道转录本的水平，并且结节区 Cic 的慢病毒过度表达加速了异常的浦肯野神经元尖峰和神经变性。这些发现强化了 Cic 在 SCA1 小脑病理生理学中的核心作用，并表明只需适度减少 Cic 即可对 SCA1 产生深远的治疗影响。