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alpha-Synuclein Inhibition of Mitochondrial Protein Import

α-突触核蛋白抑制线粒体蛋白输入

基本信息

批准号：
9044369
负责人：
J Timothy Greenamyre
金额：
$ 36.04万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044369
关键词：
Affinity Autonomic Dysfunction Binding Cardiolipins Cells Cognitive Complex Consensus Sequence Defect Disease Dopamine Environmental Risk Factor Etiology Genetic Genome Genus Hippocampus Impairment Individual Lipids Maintenance Measures Mediating Membrane Mitochondria Mitochondrial Proteins Modification N-terminal Nature Nerve Degeneration Neurodegenerative Disorders Nitrates Outer Mitochondrial Membrane Parkinson Disease Pathogenesis Phosphorylation Point Mutation Post-Translational Protein Processing Power Plants Production Protein Import Proteins RNA Splicing Reactive Oxygen Species Respiration Signal Transduction Signaling Protein Solutions Substantia nigra structure Sulfhydryl Compounds Surveys Symptoms Synapses System Therapeutic Time Variant alpha synuclein base combat dopaminergic neuron genetic manipulation mitochondrial dysfunction motor impairment mutant nitration novel overexpression oxidation oxidative damage public health relevance receptor small hairpin RNA translocase

项目摘要

DESCRIPTION (provided by applicant): Parkinson disease (PD) is a common neurodegenerative disorder resulting in motor impairment, cognitive and psychiatric symptoms and autonomic dysfunction. Genetic and environmental factors have been implicated in PD pathogenesis, and it appears that mitochondrial defects and accumulation of the synaptic protein, α- synuclein, are common to most forms of the disease. Moreover, there is evidence of a bidirectional interaction between mitochondrial dysfunction and α-synuclein accumulation. Inhibition of mitochondrial complex I leads to accretion and oligomerization of α-synuclein, and increased levels of α-synuclein cause mitochondrial impairment and production of reactive oxygen species (ROS). The nature of the interaction between α- synuclein and mitochondria remains obscure, and it is unclear whether unmodified monomeric α-synuclein is responsible for these effects, or whether posttranslational modifications which have been implicated in pathogenesis, such as oligomerization, dopamine modification, phosphorylation or nitration are important. Mitochondria contain their own genome, but it encodes only 13 proteins, so they must import about 99% of the >1000 proteins they contain. Mitochondrial protein import occurs through complex and highly regulated systems, the best understood of which recognizes N-terminal mitochondrial targeting signals (MTS) on proteins destined for import. While there is no consensus sequence, MTS characteristically form an amphipathic helix that is recognized by a receptor protein, TOM20, which is a subunit of the translocase complex of the outer mitochondrial membrane (TOM). Although monomeric α-synuclein is an intrinsically disordered protein in solution, in association with anionic lipids in membranes, it forms an amphipathic helix similar to known MTS motifs. In this context, we have strong evidence that certain forms of posttranslationally-modified α-synuclein bind specifically to TOM20 and interfere with import of mitochondrially-targeted proteins. We propose to study the interaction of α-synuclein with mitochondrial import machinery in the following aims: (1) Define the specific forms of α-synuclein that inhibit mitochondrial protein import; (2) Define key binding partners and binding parameters; (3) Determine functional consequences of α-synuclein-induced impairment of mitochondrial protein import; (4) Investigate whether blockade of mitochondrial protein import causes nigrostriatal neurodegeneration similar to α-synuclein overexpression; and (5) Examine the potential for genetic manipulation of mitochondrial import to protect against AAV2-mediated α-synuclein overexpression in substantia nigra.