Emerging pathways of dystonia pathogenesis: eIF2alpha and neuroplasticity defects in DYT6

Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1, a zinc-finger transcription factor, cause DYT6, but its neuronal targets and functions are unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1C54Y or deltaExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2alpha Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic Long Term Depression pathways, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays confirmed the functional significance of those findings. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence on the pathogenesis of unrelated forms of inherited dystonia. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1C54Y or deltaExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum肌张力障碍（Dystonia）以不自主肌肉收缩为特征。该疾病的多种亚型在遗传、表型与病因学维度均存在显著异质性，目前尚不清楚其不同亚型的发病机制是否存在共同的通路汇聚机制。锌指转录因子THAP1（THAP1）的突变可引发DYT6型肌张力障碍，但其神经元调控靶点与具体生物学功能尚未明确。本研究通过RNA测序（RNA-Seq）技术，检测了杂合型Thap1C54Y等位基因或deltaExon2等位基因对新生小鼠纹状体与小脑中基因转录特征的体内影响。富集分析得到的通路与基因本体（Gene Ontology）注释术语包括eIF2α信号通路、线粒体功能障碍、神经元投射发育、轴突导向信号通路以及突触长时程抑制通路，这些通路的调控异常呈现基因型与组织依赖性特征。电生理实验与神经突生长实验验证了上述发现的功能学意义。值得注意的是，其中多条通路近期被证实与包括DYT1型在内的其他遗传性肌张力障碍亚型相关。本研究认为，这些通路的功能异常可能代表了不同亚型遗传性肌张力障碍发病机制的共同汇聚点。本研究通过RNA测序（RNA-Seq）技术，检测了杂合型Thap1C54Y等位基因或deltaExon2等位基因对新生小鼠纹状体与小脑中基因转录特征的体内影响