# Regulations of organellar Zn2+ homeostasis and dynamics by TRPML1 in neurons

> **NIH NIH R01** · UNIVERSITY OF DENVER (COLORADO SEMINARY) · 2023 · $321,226

## Abstract

The importance of labile, unbound Zn2+ in normal brain function has been evidenced by the association of
abnormal cellular Zn2+ distributions with a series of neurological diseases such as depression, Alzheimer's
disease (AD), aging, Mucolipidosis type IV disease (MLIV), and Parkinson’s diseases. MLIV is a lysosomal
storage disease with neurodegenerative phenotype developed in childhood. The genetic mutations causing
MLIV have been identified in the gene TRPML1, which encodes a lysosomal channel permeable to cations such
as Ca2+and Zn2+. Loss of TRPML1 function resulted in elevated lysosomal Zn2+ in the fibroblasts derived from
MLIV patients. However, neither the molecular mechanisms nor the biological impacts of such Zn2+
dysregulations are understood. Our preliminary studies devised a novel sensor GZnP3 with unprecedented
sensitivity in the nanomolar range and provided the first profound evidence that TRPML1 can mobilize Zn2+ from
lysosomes and late endosomes to the cytosol in neurons. Such endolysosomal Zn2+ release is unique in neurons
and yields much greater Zn2+ signals in neurites than in the soma. Furthermore, we revealed that nanomolar
Zn2+ can reduce the axonal transport in neurons. Based on the preliminary evidence, we hypothesize that
impaired Zn2+ release from the vesicular organelles can cause neurodegeneration and contribute to the
pathogenesis of MLIV. We will utilize the MLIV cell models along with our unique genetically targeted probes to
test our hypothesis and address three specific aims: (1) We will quantify and compare the Zn2+ concentrations
among various subcellular compartments in normal and MLIV cell models that are established in human
fibroblasts and rat hippocampal neurons; (2) We will utilize our sensitive probes to investigate the correlation
between impaired endolysosomal Zn2+ release with MLIV disease and determine the transport mechanisms that
concentrate high pools of Zn2+ into endolysosomal vesicles in neurons; (3) We will examine our hypothesis that
TRPML1 regulates neuronal health and function by mediating Zn2+ release from lysosomes to the cytosol: the
released Zn2+ signals can regulate axonal transport and reduced lysosomal Zn2+ can recover the autophagic
function of lysosomes. Collectively, the proposed research will provide ultra sensitive tools for monitoring cellular
Zn2+ dynamics, develop a better understanding about the changes in organellar Zn2+ distributions and dynamics
in MLIV, characterize the correlation between endolysosomal Zn2+ release and MLIV, as well as reveal the
impacts of TRPML1-mediated Zn2+ dynamics on neuronal function. All of the above will significantly expand our
knowledge about the pathological mechanisms of MLIV disease.

## Key facts

- **NIH application ID:** 10620676
- **Project number:** 5R01NS110590-05
- **Recipient organization:** UNIVERSITY OF DENVER (COLORADO SEMINARY)
- **Principal Investigator:** Yan Qin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $321,226
- **Award type:** 5
- **Project period:** 2019-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620676

## Citation

> US National Institutes of Health, RePORTER application 10620676, Regulations of organellar Zn2+ homeostasis and dynamics by TRPML1 in neurons (5R01NS110590-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620676. Licensed CC0.

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