# The Role of SYNJ1 in Dysregulating the Basal Ganglia Function

> **NIH NIH R01** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2022 · $346,780

## Abstract

Project Summary
Regulated synaptic transmission is essential in maintaining the proper function of the brain, and mutations in
synaptic genes are often linked to neurological and neurodegenerative disorders. The goal of this project is to
uncover the molecular and cellular mechanisms of the synaptic gene, SYNJ1 (encoding synaptojanin1, synj1),
in contributing to dysfunction of the basal ganglia for motor control. Missense mutations in SYNJ1 (known as
PARK20) are associated with early-onset atypical Parkinsonism. Mice carrying the R258Q disease mutation or
missing one copy of the SYNJ1 gene (SYNJ1+/-) display motor deficits, impaired synaptic vesicle (SV) recycling
and dystrophic changes in dopaminergic axons and terminals. However, the mechanism whereby synj1 partial
loss-of-function results in the dysfunction of the dopaminergic pathway in the basal ganglia remains unclear.
Synj1 is an inositol phosphatase enriched in the axonal terminals, where it regulates SV recycling. Our
preliminary study suggested that SYNJ1 deficiency leads to midbrain-specific changes in PIP2, abnormal
presynaptic calcium signals, impaired SV recycling and enlarged presynaptic terminals in the midbrain neurons.
We hypothesize that loss of SYNJ1 dysregulates important signaling lipids, which results in aberrant calcium
channel function, altered dopamine release and impaired membrane trafficking. We will carry out an in-depth
investigation for SYNJ1 deficient mice and cultured neurons expressing recently identified SYNJ1 disease
mutations. We will use genetically encoded calcium indicators and electrophysiology to analyze presynaptic
calcium; immunochemistry combined with electron microscopy to investigate membrane trafficking; and a novel
optical dopamine sensor in combination with biochemical and behavioral analyses to examine dopamine
transmission. By implementing the proposed research plan, we aim to reveal key pathogenic processes
responsible for the impairment of the dopaminergic signaling in the basal ganglia and common signaling
pathways shared by other synaptic genes in neurodegeneration. The result of this study is also expected to gain
insights in synj1-mediated cell type-specific regulation and provide new perspectives for novel therapeutics.

## Key facts

- **NIH application ID:** 10407516
- **Project number:** 5R01NS112390-04
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Ping-Yue Pan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,780
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407516

## Citation

> US National Institutes of Health, RePORTER application 10407516, The Role of SYNJ1 in Dysregulating the Basal Ganglia Function (5R01NS112390-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10407516. Licensed CC0.

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