PINK1 protects neurons against mutant Tau pathology

项目总结/文摘

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.