# PINK1 protects neurons against mutant Tau pathology

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $67,507

## Abstract

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.

## Key facts

- **NIH application ID:** 10066023
- **Project number:** 1F32AG069343-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Britney Nola Lizama
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,507
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066023

## Citation

> US National Institutes of Health, RePORTER application 10066023, PINK1 protects neurons against mutant Tau pathology (1F32AG069343-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10066023. Licensed CC0.

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