Unconventional protein secretion-mediated protein quality control in health and diseases

路易体（Lewy bodies，LB）是帕金森病（Parkinsons disease，PD）的典型标志。这些内含物的主要成分是α-突触核蛋白（α-syn），一种具有错误折叠和聚集内在倾向的蛋白质。在PD患者中，首先在嗅球和背侧运动核中观察到的α-syn包涵体逐渐扩散到整个大脑。进一步的研究发现，健康的胚胎多巴胺神经元移植到PD患者发展LB点表明神经元到神经元的α-syn传输的诱人的可能性。随后的工作证实，合成的a-syn预形成的原纤维（PFF）可以被神经元吸收，引起内源性a-syn错误折叠成不溶性路易样内含物。总的来说，这些研究导致了PD的朊病毒假说，其中错误折叠的-syn提供了用于接种新聚集体、传播错误折叠的a-syn和相关细胞毒性的模板。因此，-syn传播是在开发新的PD疗法中待探索的可行的新靶点。 突触核蛋白的细胞间传递包括两个关键步骤：供体神经元分泌突触核蛋白和受体神经元摄取突触核蛋白。 错误折叠相关蛋白分泌（MAPS）是最近发现的蛋白质质量控制过程，其选择性地输出错误折叠的胞质蛋白，包括α-syn。通过MAPS的分泌需要膜定位的去泛素化酶USP 19，其将异常多肽募集到内质网（ER）表面以促进其并入与ER紧密结合的晚期内体。 当晚期内体与质膜融合时，错误折叠的蛋白质被分泌到细胞外环境。 释放的错误折叠蛋白的命运目前尚不清楚。 我们最近的研究表明，哺乳动物细胞可以通过内吞作用内化错误折叠蛋白，但目前还不清楚它们是否具有一个或多个错误折叠蛋白的受体。 内化的蛋白质是否能在被溶酶体降解之前造成损伤也不清楚。 该建议是阐明的生理相关性的MAPS途径的特征之间的相互作用分泌的错误折叠的蛋白质和靶细胞。

Proteinaceous inclusions termed Lewy bodies (LBs) is a classical hallmark of Parkinsons disease (PD). The primary component of these inclusions is alpha-synuclein (a-syn), a protein with an intrinsic propensity to misfold and aggregate. In PD patients, alpha-syn inclusions first observed in the olfactory bulb and the dorsal motor nucleus, progressively spread throughout the brain. Further findings that healthy embryonic dopamine neurons transplanted into PD patients developed LBs points suggest the tantalizing possibility of neuron-to-neuron transmission of a-syn. Subsequent work comfirmed that synthetic a-syn pre-formed fibrils (PFFs) can be taken up by neurons, eliciting the misfolding of endogenous -syn into insoluble Lewy-like inclusions. Collectively, these studies led to the prion hypothesis of PD, wherein misfolded -syn provides a template for seeding new aggregates, propogating misfolded a-syn and associated cytotoxicity. Thus, that propagation of -syn is a viable new target to be explored in the development of new PD therapies. The intercellular transmission of synuclien consists of two key steps: the secretion of synuclein from a donor neuron and its uptake by a recipient neuron. Misfolding-associated protein secretion (MAPS) is a recently discovered protein quality control process that selectively exports misfolded cytosolic proteins including a-syn. Secretion through MAPS requires the membrane localized deubiquitinase USP19, which recruits aberrant polypeptides to endoplasmic reticulum (ER) surface to facilitate their incorporation into to late endosomes that are in tight association with the ER. Misfolded proteins are secreted to the extracellular milieu when late endosomes fuse with the plasma membrane. The fate of the released misfolded proteins is current unknown. Our recent studies suggest that mammalian cells can internalize misfolded proteins via endocytosis, but it is unclear whether they possess one or more receptors for misfolded proteins. Whether internalized proteins can impose damage prior to degradation by the lysosome is also unclear. The proposal is to elucidate the physiological relevance of the MAPS pathway by characterizing the interplay between secreted misfolded proteins and target cells.