# Chloride Homeostasis in Lysosomal Function and Parkinson's Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $604,578

## Abstract

Parkinson's disease (PD) is a progressive and degenerative disorder of the brain. It is pathologically
characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). The key
events driving the pathogenesis in PD are not completely understood. The long-term objective of my research
is to understand the molecular and cellular processes by which neurons respond to stress and how dysfunction
of these responsive mechanisms contributes to neurodegenerative process. I propose to investigate a new
molecular regulatory process of lysosomal chloride and its role in PD pathogenesis. Chloride ion is the most
abundant anion in both extra- and intracellular spaces of animal cells. No longer regarded as an inert anion,
chloride is found to play discrete roles in cells and its homeostasis needs to be tightly regulated at a subcellular
organelle level. Lysosomal chloride is important for the function of acidic hydrolases. In addition to this general
role, lysosomal chloride itself also has specific roles affecting lysosomal functions such as binding directly to
cathepsin C to regulate its activity. Lysosomal chloride is mainly regulated by chloride channel 7 (CLC-7) in
complex with its beta subunit Ostm-1. Loss of either protein severely comprises lysosomal chloride
homeostasis, reduces lysosomal degradation capacity, and causes accumulation of lysosomal storage
materials and autophagosomes, leading to diseases in human and rodent models including neuronal damages
and degeneration. How CLC-7 is regulated remains largely unknown and no studies have ever reported its
involvement in PD pathogenesis. We discovered unexpectedly a regulatory link between leucine-rich repeat
kinase 2 (LRRK2), one of the most common genetic determinants associated with PD, and CLC-7. Our new
preliminary data show a direct interaction between LRRK2 and CLC-7. This interaction is pathogenically
enhanced by LRRK2 G2019S mutation and by oxidative stress, leading to aberrantly high level of lysosomal
chloride and reduced lysosomal activities. We hypothesize that LRRK2 interacts with CLC-7 to modulate
lysosomal chloride homeostasis and pathogenic mutant LRRK2G2019S dysregulates this process and impairs
lysosomal functions. We propose to assess the molecular effects of LRRK2 on CLC-7 function in DA neurons
derived from iPSCs of PD patients (aim I), assess the cellular effects of aberrant LRRK2-CLCL-7
interaction under genetic and oxidative stress on lysosomal functions in DA neurons derived from
control and PD patient iPSCs (aim II); assess the molecular and cellular effects of LRRK2 on lysosomal
CLC-7, chloride, and functions in animal models of PD (aim III), and assess the lysosomal LRRK2, CLC-7, and
chloride in postmortem brains of PD patients (aim IV). The study will identify the key process that controls
lysosomal chloride, establish its role in PD cytopathogenesis, and possibly reveal new therapeutic targets and
biomarkers for the disease.

## Key facts

- **NIH application ID:** 10656542
- **Project number:** 5R01NS125317-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ZIXU MAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $604,578
- **Award type:** 5
- **Project period:** 2022-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656542

## Citation

> US National Institutes of Health, RePORTER application 10656542, Chloride Homeostasis in Lysosomal Function and Parkinson's Disease (5R01NS125317-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10656542. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*