Dendritic simplification and synaptic loss represent major structural correlates of dementia in Alzheimer?s disease (AD) and frontotemporal dementia (FTD). Mutations in the microtubule-associated protein tau are a major cause of FTD and increase the risk of developing AD. Mutations in valosin-containing protein (VCP) have also been linked to familial FTD. In the prior project period, we discovered that dendritic calcium dyshomeostasis, dysregulated mitophagy and altered protein phosphorylation contribute to dendritic shrinkage in several models of neurodegeneration. We also discovered a novel interaction between VCP and the neuroprotective kinase PTEN-induced kinase 1 (PINK1). VCP is a multifunctional protein implicated in protein degradation, vesicular transport and Golgi remodeling, and these functions are mediated by distinct VCP cofactors. Based on preliminary data, we hypothesize that PINK1 interacts with VCP to prevent tau- mediated dendritic shrinkage. We will utilize primary rodent cortical neurons and human iPSC-derived neurons to study quality control mechanisms that contribute to neuroprotection against tau-mediated degeneration of dendritic arbors and spines. We will also assess the neuroprotective potential of upregulating PINK1 signaling in vitro and in vivo. Completion of these studies will reveal how proteins implicated in different neurodegenerative diseases function together to protect against tau-mediated neurodegeneration.

Public Health Relevance

Mutations in the gene encoding the protein tau cause frontotemporal dementia and/or increase the risk of developing Alzheimer?s dementia. Tau plays important roles in brain cells (neurons) regulating the cytoskeleton, which is essential for formation and maintenance of the communication network that underlies neuronal function. We have discovered a novel neuroprotective pathway involving two proteins whose gene mutations contribute to frontotemporal dementia and Parkinson?s-related dementia. This proposal focuses upon understanding the mechanism(s) and neuroprotective potential of this pathway in patient-derived neuronal cells and a mouse model.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Wise, Bradley C
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University of Pittsburgh
Schools of Medicine
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Verma, Manish; Wills, Zachary; Chu, Charleen T (2018) Excitatory Dendritic Mitochondrial Calcium Toxicity: Implications for Parkinson's and Other Neurodegenerative Diseases. Front Neurosci 12:523
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Kagan, V E; Jiang, J; Huang, Z et al. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140-51
Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) ?-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78

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