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Abstract：
Aggregation of aberrant proteins is a common pathological hallmark in neurodegeneration such as polyglutamine (polyQ) and other repeat-expansion diseases. Here through overexpression of ataxin3 C-terminal polyQ expansion in Drosophila gut enterocytes, we generated an intestinal obstruction model of spinocerebellar ataxia type3 (SCA3) and reported a new role of nuclear-associated endosomes (NAEs)-the delivery of polyQ to the nucleoplasm. In this model, accompanied by the prominently increased RAB5-positive NAEs are abundant nucleoplasmic reticulum enriched with polyQ, abnormal nuclear envelope invagination, significantly reduced endoplasmic reticulum, indicating dysfunctional nucleocytoplasmic trafficking and impaired endomembrane organization. Consistently, Rab5 but not Rab7 RNAi further decreased polyQ-related NAEs, inhibited endomembrane disorganization, and alleviated disease model. Interestingly, autophagic proteins were enriched in polyQ-related NAEs and played non-canonical autophagic roles as genetic manipulation of autophagic molecules exhibited differential impacts on NAEs and SCA3 toxicity. Namely, the down-regulation of Atg1 or Atg12 mitigated while Atg5 RNAi aggravated the disease phenotypes both in Drosophila intestines and compound eyes. Our findings, therefore, provide new mechanistic insights and underscore the fundamental roles of endosome-centered nucleocytoplasmic trafficking and homeostatic endomembrane allocation in the pathogenesis of polyQ diseases.
摘要：
异常蛋白质的聚集是神经变性如聚谷氨酰胺(polyQ)和其他重复扩增疾病中的常见病理标志。通过在果蝇肠肠细胞中过表达ataxin3C末端polyQ扩增，我们建立了脊髓小脑性共济失调类型3(SCA3)的肠梗阻模型,并报道了核相关内体(NAEs)的新作用-将polyQ递送至核质.在这个模型中,伴随着显著增加的RAB5阳性NAEs是富含polyQ的大量核质网，异常的核包膜内陷，内质网显著减少，表明功能失调的核质运输和受损的内膜组织。始终如一，Rab5而不是Rab7RNAi进一步降低polyQ相关NAE，抑制内膜解体，缓解疾病模型。有趣的是,自噬蛋白在与polyQ相关的NAEs中富集，并发挥非经典自噬作用，因为自噬分子的遗传操作对NAEs和SCA3毒性表现出不同的影响。即,Atg1或Atg12的下调减轻，而Atg5RNAi加重果蝇肠和复眼的疾病表型。我们的发现,因此,提供新的机制见解，并强调以内体为中心的核质运输和稳态内膜分配在polyQ疾病发病机理中的基本作用。
