Prevention of alpha-synuclein deSUMOylation as a Parkinson's therapeutic target

预防α-突触核蛋白去SUMO化作为帕金森病的治疗靶点

基本信息

批准号：
10360242
负责人：
YongHwan Kim
金额：
$ 43.8万
依托单位：
DELAWARE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360242
关键词：
Adopted Affect Age Anatomy Axon Basic Science Behavioral Biochemical Brain Brain Diseases Cell Death Cell Line Cell model Cells Chemicals Chronic Collaborations Corpus striatum structure Data Disease Disease model Dominant-Negative Mutation Dopaminergic Cell Electrophysiology (science)Enzymes Functional disorder Gender Generations Goals Half-Life Health Human Impairment In Vitro Injections Institutes Korea LRRK2 gene Learning Lewy Bodies Ligase MPTP Poisoning MPTP treatment Mass Spectrum Analysis Measures Mediating Methods Midbrain structure Modeling Molecular Motor Mus Nerve Neurodegenerative Disorders Neurons Outcome Oxidative Stress Parkinson Disease Parkinsonian Disorders Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Pharmacodynamics Play Post-Translational Protein Processing Prevention Process Proteins Proteomics Publications RNA Interference Rattus Reactive Oxygen Species Reagent Regulation Reporting Research Institute Research Training Resistance Role Sampling Small Interfering RNA Solubility Substantia nigra structure Sumoylation Pathway Symptoms Synapses Synaptic Transmission Techniques Testing The Sun Therapeutic Toxic effect Transgenic Mice Ubiquitin United States Validation Wild Type Mouse alpha synuclein brain tissue cytotoxicity dopamine transporter dopaminergic neuron gamma-Glutamyl Hydrolase graduate student in vivo in vivo Model inhibitor insight mouse model neuron loss neuroprotection novel overexpression pars compacta prevent protein aggregation protein degradation protein misfolding sulfoenolpyruvate synuclein therapeutic target training opportunity

项目摘要

A form of post-translational modifications (PTM), SUMOylation of target proteins has been implicated in Parkinson’s disease pathology (10), however, it is still debatable as to whether SUMOylation contributes to the disease or is a protective mechanism (9). Our recent publication using mouse models suggest that the overexpression of SUMO conjugase, Ubc9 protects dopaminergic axon tips in the striatum and cell bodies in the SN from the known PD-inducing reagent (MPTP) that results in Parkinsonian symptoms (Fig 1) (12). In addition, the MPTP treatment results in decreased SUMOylation of α-synuclein in mouse striatum (Fig 2), suggesting that MPTP-induced toxicity stimulates the deSUMO enzyme, SENP for removing SUMOs from α-synuclein, which may be associated with dopaminergic neuronal loss in the SN. Our recent results support that SENPs can be regulatory targets to prevent the deSUMOylation process that may be a part of protein aggregation and neuronal death pathway. Particularly, we identified consistently in N27 cells, mouse models and human Parkinson’s disease patients SNpc that SENP1 among known 6-7 mammalian SENPs, was significantly upregulated by MPP+ or the preformed fibrils (PFF) of α-synuclein-mediated toxicity (Figs 3,4). However, the MPTP induced toxicity does not recapitulate the typical protein aggregation-mediated PD pathology. Therefore, we adopt the recently established method using the preformed fibril (PFF) of α-synuclein for mimicking protein aggregation-mediated PD pathology. We test the hypothesis that blocking deSUMOylating enzyme, SENP1 prevents PFF-mediated toxicity in dopaminergic neurons. Using SENP1 RNAi, dominant negative, or chemical inhibitors, we will assess the target validation of SENP1 inhibition to enhance protein stability/solubility and to prevent PFF-induced protein mis-folding and aggregation. In addition, we will also verify that SENP1 expression in the SN from additional human PD midbrains was significantly higher than that in age- and gender-matched healthy controls using additional 10 samples per group. In parallel, we will assess the proteomics shifts in SUMOylation and SENPs in PFF-injected mouse brains using mass spectrometry. This study will provide new strategies for protecting dopaminergic neurons from protein aggregation-mediated toxicity that leads to Parkinson’s disease. Our potential outcome will result in meaningful publications and reveal novel target validation, as well as offering great opportunities for underrepresented (under)graduate students at an HBCU to learn essential scientific techniques and unique approaches from leading scientific groups.