# Chaperone-mediated Autophagy and Synaptic Dysfunction in Parkinson's Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $494,046

## Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the
degenerative loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. Studies of cellular and
animal models and postmortem PD patient brains reveal that synaptic dysfunction triggered by environmental
and genetic stress is an early event in PD pathogenesis. However, the precise and key mechanisms that
underlie synaptic dysfunction in PD remain to be defined. The vacuolar (H+)-ATPase (V-ATPase) is an ATP-
dependent proton pump involved in acidifying synaptic vesicles and plays a critical role in multiple steps of
synaptic vesicle life cycle such as fusion with pre-synaptic membrane and neurotransmitter release/reloading.
Our preliminary studies show that synaptic V-ATPase may be controlled by chaperone-mediated autophagy
(CMA), a lysosome-based process specialized in disposing oxidized or damaged proteins for degradation to
maintain cellular function under stress. Notably, CMA is inhibited by multiple stress conditions associated with
PD including aging, neurotoxic stress, oxidative stress, ER stress, and genetic stress. However, whether and
how cellular stress signals and CMA engage V-ATPase to modulate synaptic function is still unknown. In the
current project, by utilizing multiple model systems, including cutting-edge human induced pluripotent stem cell
(iPSC) model, in vivo rodent models (ER and genetic stress of rodent brains), and postmortem PD patient
brains, we aim to determine whether CMA directly degrades damaged components of synaptic V-ATPase to
maintain synaptic vesicle function under stress, and whether loss of adequate CMA activity impairs synaptic
function in PD. First, we will determine biochemically, cell biologically, and electro-physiologically if CMA
directly regulates synaptic V-ATPase and synaptic function in DA neurons derived from human iPSCs. Second,
we will test if multiple stress conditions related to PD regulate synaptic V-ATPase and function via CMA in
human iPSC-derived DA neurons. Last, we will assess the regulation and role of CMA–V-ATPase–synaptic
vesicle pathway in multiple PD animal models and in postmortem brains from PD patients. Our proposed study
will significantly advance our understanding of how stress regulates synaptic vesicle, reveal a key pathogenic
mechanism underlying synaptic failure in PD, and offer new opportunities for developing
diagnostics/biomarkers and more effective prevention and treatment strategies for the disease.

## Key facts

- **NIH application ID:** 10427401
- **Project number:** 5R01NS107505-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ZIXU MAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $494,046
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427401

## Citation

> US National Institutes of Health, RePORTER application 10427401, Chaperone-mediated Autophagy and Synaptic Dysfunction in Parkinson's Disease (5R01NS107505-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10427401. Licensed CC0.

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