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Regulations of organellar Zn2+ homeostasis and dynamics by TRPML1 in neurons

TRPML1 对神经元细胞器 Zn2 稳态和动力学的调节

基本信息

批准号：
10620676
负责人：
Yan Qin
金额：
$ 32.12万
依托单位：
UNIVERSITY OF DENVER (COLORADO SEMINARY)
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620676
关键词：
Address Affect Aging Alzheimer&apos s Disease Axonal Transport Biological Biosensor Brain Brain region Cations Cell model Cells Chelating Agents Childhood Cytosol DNA Sequence Alteration Data Detection Disease Dominant-Negative Mutation Engineering Etiology Exhibits Fibroblasts Ganglioside Sialidase Deficiency Disease Genes Goals Health Hela Cells Hippocampus Homeostasis Human Impairment Ions Kinetics Knowledge Lead Lysosomal Storage Diseases Lysosomes Maps Measures Mediating Mental Depression Metals Mitochondria Mitochondrial Matrix Molecular Monitor Mutation Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Organelles Parkinson Disease Pathogenesis Pathologic Patients Permeability Physiological Process Proteins RNA Interference Rattus Regulation Research Role Series Severities Signal Transduction Specificity Testing Time Vesicle Work improved inhibitor injured late endosome nanomolar nervous system disorder neurite growth neurodegenerative phenotype neuronal cell body new therapeutic target next generation novel postsynaptic presynaptic sensor small molecule tool vesicular release

项目摘要

The importance of labile, unbound Zn2+ in normal brain function has been evidenced by the association of abnormal cellular Zn2+ distributions with a series of neurological diseases such as depression, Alzheimer's disease (AD), aging, Mucolipidosis type IV disease (MLIV), and Parkinson’s diseases. MLIV is a lysosomal storage disease with neurodegenerative phenotype developed in childhood. The genetic mutations causing MLIV have been identified in the gene TRPML1, which encodes a lysosomal channel permeable to cations such as Ca2+and Zn2+. Loss of TRPML1 function resulted in elevated lysosomal Zn2+ in the fibroblasts derived from MLIV patients. However, neither the molecular mechanisms nor the biological impacts of such Zn2+ dysregulations are understood. Our preliminary studies devised a novel sensor GZnP3 with unprecedented sensitivity in the nanomolar range and provided the first profound evidence that TRPML1 can mobilize Zn2+ from lysosomes and late endosomes to the cytosol in neurons. Such endolysosomal Zn2+ release is unique in neurons and yields much greater Zn2+ signals in neurites than in the soma. Furthermore, we revealed that nanomolar Zn2+ can reduce the axonal transport in neurons. Based on the preliminary evidence, we hypothesize that impaired Zn2+ release from the vesicular organelles can cause neurodegeneration and contribute to the pathogenesis of MLIV. We will utilize the MLIV cell models along with our unique genetically targeted probes to test our hypothesis and address three specific aims: (1) We will quantify and compare the Zn2+ concentrations among various subcellular compartments in normal and MLIV cell models that are established in human fibroblasts and rat hippocampal neurons; (2) We will utilize our sensitive probes to investigate the correlation between impaired endolysosomal Zn2+ release with MLIV disease and determine the transport mechanisms that concentrate high pools of Zn2+ into endolysosomal vesicles in neurons; (3) We will examine our hypothesis that TRPML1 regulates neuronal health and function by mediating Zn2+ release from lysosomes to the cytosol: the released Zn2+ signals can regulate axonal transport and reduced lysosomal Zn2+ can recover the autophagic function of lysosomes. Collectively, the proposed research will provide ultra sensitive tools for monitoring cellular Zn2+ dynamics, develop a better understanding about the changes in organellar Zn2+ distributions and dynamics in MLIV, characterize the correlation between endolysosomal Zn2+ release and MLIV, as well as reveal the impacts of TRPML1-mediated Zn2+ dynamics on neuronal function. All of the above will significantly expand our knowledge about the pathological mechanisms of MLIV disease.

不稳定的、未结合的Zn2+在正常脑功能中的重要性已被与