# Role of LRRK2 in dopaminergic transmission

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $341,250

## Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting
millions of people. Many of the psychomotor symptoms are attributed to the degeneration of
dopaminergic neurons innervating the striatum. Emerging evidence suggests that synaptic
dysfunction is an early event in the pathogenesis of the disease occurring prior to the onset of
symptoms. In order to develop more effective therapeutic strategies, we need a better
understanding of the underlying mechanisms of synaptic dysfunction of PD. Mutations in
Leucinerich-repeat-kinase 2 (LRRK2), the newly identified causative gene for PARK8 type PD
with autosomal dominant inheritance, are the MOST PREVALENT genetic causes in both
familial and sporadic PD. Whereas plenty of effort is being directed to understand the role of
LRRK2 in the pathogenesis of PD, little is known about the normal physiological functions of
LRRK2 in DA neurotransmission and their contributions to PD. Recently a transgenic mouse
model with over-expression of human LRRK2-R1441G has been shown to recapitulate robust
motor behavioral, neurochemical and pathological features of PD. At the level of pathology, the
early and most robust phenotype is the axonopathy of the nigrostriatal dopaminergic projection.
Our preliminary data has shown age dependent progressive deficits of dopaminergic synaptic
function in this model. Therefore, in this study, we plan to determine how LRRK2 affects
dopamine release by comparing these processes in two mouse models with either high levels of
mutated LRRK2 or no LRRK2. We hypothesize that pathogenic LRRK2 R1441G mutation 1)
impairs synaptic vesicle recycling, which in turn increases cytosolic dopamine level in pre-
synaptic terminals leading to axonal degeneration in the end, and 2) abolishes the  maturation of
the somatodendritic D2-autoreceptor response, which in turn lead to excitatory toxicity. We will
further explore whether molecules of the endocytosis machinery mediate the dopamine synaptic
transmission deficits and the axonal degeneration among all the aspects of LRRK2 induced
pathogenesis. We will utilize a combination of electrophysiology, optical imaging, biochemistry,
and mouse genetics to uncover mechanisms underlying the dopamine deficit in PD. These
findings will likely provide new insights into pathogenesis of PD and open new avenues for
therapeutic intervention.

## Key facts

- **NIH application ID:** 9952425
- **Project number:** 5R01NS097530-05
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** HUI ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,250
- **Award type:** 5
- **Project period:** 2016-09-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952425

## Citation

> US National Institutes of Health, RePORTER application 9952425, Role of LRRK2 in dopaminergic transmission (5R01NS097530-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9952425. Licensed CC0.

---

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