The Role of SYNJ1 in Dysregulating the Basal Ganglia Function

SYNJ1 在基底神经节功能失调中的作用

• 批准号: 10199081
• 负责人: Ping-Yue Pan
• 金额: $ 42.26万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199081
• 关键词: Address; Affect; Axon; Basal Ganglia; Behavioral; Biochemical; Brain; Brain Diseases; Brain region; Calcium; Calcium Channel; Calcium Signaling; Clathrin; Corpus striatum structure; Data; Defect; Disease; Dopamine; Down Syndrome; Electron Microscopy; Electrophysiology (science); Endocytosis; Endoplasmic Reticulum; Exocytosis; FRAP1 gene; Functional disorder; Genes; Goals; Hippocampus (Brain); Homeostasis; Human; Immunochemistry; Impairment; Induced Mutation; Inositol; Investigation; Knowledge; Lead; Link; Lipids; Mediating; Membrane; Memory; Methods; Midbrain structure; Missense Mutation; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Optical reporter; Optics; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Perinatal mortality demographics; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Play; Point Mutation; Presenile Alzheimer Dementia; Presynaptic Terminals; Process; Recycling; Regulation; Research; Role; SYNJ1 gene; Second Messenger Systems; Signal Pathway; Signal Transduction; Substantia nigra structure; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptic Vesicles; Testing; Variant; Work; age related; atypical parkinsonism; base; calcium indicator; cell type; dopaminergic neuron; early onset; inhibitory neuron; insight; loss of function; loss of function mutation; mitochondrial dysfunction; motor control; motor deficit; motor disorder; motor impairment; mutant; nervous system disorder; novel; novel therapeutics; overexpression; presynaptic; programs; receptor function; sensor; synaptic function; trafficking; transmission process; voltage

Project Summary Regulated synaptic transmission is essential in maintaining the proper function of the brain, and mutations in synaptic genes are often linked to neurological and neurodegenerative disorders. The goal of this project is to uncover the molecular and cellular mechanisms of the synaptic gene, SYNJ1 (encoding synaptojanin1, synj1), in contributing to dysfunction of the basal ganglia for motor control. Missense mutations in SYNJ1 (known as PARK20) are associated with early-onset atypical Parkinsonism. Mice carrying the R258Q disease mutation or missing one copy of the SYNJ1 gene (SYNJ1+/-) display motor deficits, impaired synaptic vesicle (SV) recycling and dystrophic changes in dopaminergic axons and terminals. However, the mechanism whereby synj1 partial loss-of-function results in the dysfunction of the dopaminergic pathway in the basal ganglia remains unclear. Synj1 is an inositol phosphatase enriched in the axonal terminals, where it regulates SV recycling. Our preliminary study suggested that SYNJ1 deficiency leads to midbrain-specific changes in PIP2, abnormal presynaptic calcium signals, impaired SV recycling and enlarged presynaptic terminals in the midbrain neurons. We hypothesize that loss of SYNJ1 dysregulates important signaling lipids, which results in aberrant calcium channel function, altered dopamine release and impaired membrane trafficking. We will carry out an in-depth investigation for SYNJ1 deficient mice and cultured neurons expressing recently identified SYNJ1 disease mutations. We will use genetically encoded calcium indicators and electrophysiology to analyze presynaptic calcium; immunochemistry combined with electron microscopy to investigate membrane trafficking; and a novel optical dopamine sensor in combination with biochemical and behavioral analyses to examine dopamine transmission. By implementing the proposed research plan, we aim to reveal key pathogenic processes responsible for the impairment of the dopaminergic signaling in the basal ganglia and common signaling pathways shared by other synaptic genes in neurodegeneration. The result of this study is also expected to gain insights in synj1-mediated cell type-specific regulation and provide new perspectives for novel therapeutics.

项目总结