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

健康和疾病中非常规蛋白质分泌介导的蛋白质质量控​​制

• 批准号: 9549992
• 负责人: Yihong Ye
• 金额: $ 56.27万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9549992
• 关键词: Brain; Cell membrane; Cells; Development; Disease; Embryo; Endocytosis; Endoplasmic Reticulum; Goals; Golgi Apparatus; Health; Lewy Bodies; Lysosomes; Mammalian Cell; Mediating; Membrane; Modeling; Neurons; Parkinson Disease; Pathway interactions; Patients; Peptide Signal Sequences; Physiological; Process; Protein Export Pathway; Protein Secretion; Proteins; Quality Control; Recruitment Activity; Research Project Grants; Surface; Transplantation; Work; alpha synuclein; cytotoxicity; dopaminergic neuron; dorsal motor nucleus; extracellular; late endosome; misfolded protein; olfactory bulb; polypeptide; prion hypothesis; receptor; synuclein; tau Proteins; transmission process; uptake

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.

蛋白质包涵体称为路易小体(LBS)，是帕金森氏病(PD)的典型特征。这些包涵体的主要成分是α-突触核蛋白(a-syn)，这是一种具有错误折叠和聚集的固有倾向的蛋白质。在帕金森病患者中，α-SYN包涵体首先在嗅球和背侧运动核中观察到，然后逐渐扩散到整个大脑。进一步的研究发现，将健康的胚胎多巴胺神经元移植到帕金森病患者体内后，出现了LBS点，这表明a-syn具有诱人的神经元到神经元传递的可能性。后来的工作证实，合成的α-SYN预形成的纤维(PFF)可以被神经元摄取，导致内源性SYN错误折叠成不溶性的路易样包裹体。总而言之，这些研究导致了帕金森病的普恩假说，其中错误折叠的SYN提供了一个模板，用于播种新的聚集体，繁殖错误折叠的a-SYN及其相关的细胞毒性。因此，-SYN的传播是开发新的PD治疗方法的一个可行的新靶点。 突触素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(MAP)是最近发现的一种蛋白质质量控制过程，它选择性地输出错误折叠的胞浆蛋白，包括a-syn。MAP的分泌需要膜上定位的脱泛素酶USP19，它将异常的多肽招募到内质网(ER)表面，促进它们整合到与内质网密切相关的晚期内体中。当晚期内体与质膜融合时，错误折叠的蛋白质会分泌到细胞外环境中。 释放的错误折叠蛋白质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将错误折叠的蛋白质内化，但目前尚不清楚它们是否拥有错误折叠蛋白质的一个或多个受体。内化的蛋白质是否会在溶酶体降解之前造成损害也是不清楚的。我们的建议是通过表征分泌的错误折叠蛋白和靶细胞之间的相互作用来阐明MAPS途径的生理学相关性。