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.

称为路易体 (LB) 的蛋白质内含物是帕金森病 (PD) 的经典标志。这些内含物的主要成分是 α-突触核蛋白 (a-syn)，这是一种具有错误折叠和聚集内在倾向的蛋白质。在帕金森病患者中，α-syn 内含物首先在嗅球和背运动核中观察到，随后逐渐扩散到整个大脑。进一步的发现表明，移植到帕金森病患者体内的健康胚胎多巴胺神经元产生了 LB 点，这表明神经元间 a-syn 传递的可能性是诱人的。随后的工作证实，合成的α-syn预形成原纤维（PFF）可以被神经元吸收，引起内源性α-syn错误折叠成不溶性的路易样内含物。总的来说，这些研究提出了PD的朊病毒假说，其中错误折叠的-syn提供了播种新聚集体、传播错误折叠的a-syn和相关细胞毒性的模板。因此，-syn 的传播是新 PD 疗法开发中需要探索的一个可行的新靶点。 突触核蛋白的细胞间传递由两个关键步骤组成：供体神经元分泌突触核蛋白以及受体神经元摄取突触核蛋白。 错误折叠相关蛋白分泌 (MAPS) 是最近发现的一种蛋白质质量控​​制过程，可选择性输出包括 a-syn 在内的错误折叠胞浆蛋白。通过 MAPS 的分泌需要膜定位的去泛素酶 USP19，它将异常多肽招募到内质网 (ER) 表面，以促进它们掺入与 ER 紧密相关的晚期内体。 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质的命运目前未知。 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的蛋白质，但尚不清楚它们是否拥有一种或多种错误折叠蛋白质的受体。 内化蛋白是否会在被溶酶体降解之前造成损害还不清楚。 该提案旨在通过表征分泌的错误折叠蛋白与靶细胞之间的相互作用来阐明 MAPS 途径的生理相关性。