PINK1 protects neurons against mutant Tau pathology

PINK1 保护神经元免受突变 Tau 病理的影响

• 批准号: 10066023
• 负责人: Britney Nola Lizama
• 金额: $ 6.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066023
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease patient; Atrophic; Autopsy; Binding; Biochemistry; Biological Assay; Calcium; Cell Culture Techniques; Central Nervous System Diseases; Cerebral cortex; Data; Dendrites; Disease; Etiology; Exhibits; Fibroblasts; Frontotemporal Dementia; Genetic; Goals; Homeostasis; Human; Image; In Vitro; Inherited; Knockout Mice; Laboratories; Length; Link; Mediating; Microtubules; Midbrain structure; Mitochondria; Modeling; Molecular Biology; Molecular Chaperones; Morphogenesis; Mutation; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuronal Injury; Neurons; PTEN gene; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Protein Biochemistry; Protein Biosynthesis; Proteins; Public Health; Quality Control; Risk; Role; Signal Transduction; Structure; Tauopathies; Testing; Therapeutic; Tissues; Toxin; Variant; age related; base; brain cell; design; early onset; human disease; in vivo; in vivo Model; induced pluripotent stem cell; insight; knock-down; loss of function; multicatalytic endopeptidase complex; neuron loss; neuroprotection; novel; overexpression; prevent; protein degradation; protein protein interaction; proteostasis; targeted treatment; tau Proteins; tau function; tau mutation; tau phosphorylation; trafficking; valosin-containing protein

Project Summary/Abstract Abstract: Proteostasis is tightly regulated, requiring efficient protein synthesis, trafficking, and degradation. Protein accumulation, mislocalization, and dendritic simplification are pathological features of neurodegenerative diseases, including Alzheimer’s disease (AD) Frontotemporal Dementia (FTD), Parkinson’s disease (PD) and PD with dementia (PDD). Despite variations in genetic and environmental etiology, these diseases share a common feature of aberrant Tau function, localization, or turnover. The Tau mutation A152T has been linked to AD, FTD, and PDD. Tau-A152T increases Tau phosphorylation, reduces microtubule extension, and causes neuronal death. PTEN-inducible kinase 1 (PINK1) expression is neuroprotective in a wide range of genetic and toxin-based models of neurodegeneration. Prior studies from our group show that subcellular pools of PINK1 play divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Additionally, we found that cytosolic PINK1 is sufficient for maintaining dendrite length and binds with Valosin-containing Protein (VCP/p97), an essential type II AAA+ protein involved in proteostasis pathways and degradation of substrates. My preliminary data reveal that increased PINK1 expression protects neurons against mutant Tau-mediated dendritic simplification and promotes mutant Tau degradation. Given these data, I hypothesize that PINK1 prevents mutant Tau (Tau-A152T) pathology and promotes mutant Tau degradation through PINK1 interaction with VCP. Using a combination of biochemistry, molecular biology, imaging and cell culture techniques, I will test the hypothesis that elevated PINK1 expression will reverse mutant Tau pathology, specifically dendritic atrophy, phosphorylation, and mislocalization (Aim 1), and test whether PINK1 promotes mutant Tau degradation via VCP (Aim 2). Upon completion of these aims, I will have identified novel pathways in which PINK1 is neuroprotective, which will not only have high impact for planning PD- and PDD-targeted therapies, but may also have broad application for AD, FTD, and other tauopathies.

项目总结/文摘