# Synaptic Dysfunction and Energy Failure in Parkinson's Disease

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2023 · $437,429

## Abstract

Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease. Loss of
substantia nigra compacta (SNc) dopaminergic projections and decreased striatal dopamine
levels are the characteristic features of PD. Emerging evidence suggest that synaptic
dysfunction of dopamine neurons is an early event in the pathogenesis of PD occurring prior to
the onset of symptoms. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the
most prevalent causes of familial and sporadic PD, demonstrating an unprecedented significant
role in PD pathogenesis. 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 most robust phenotype is the
axonopathy of the nigrostriatal dopaminergic projection, accompanied by age-dependent
hyperphosphorylated tau and DA transmission deficits. Both genetic and environmental causes
of PD have highlighted the importance of mitochondrial dysfunction in the pathogenesis of PD.
Mitochondrial trafficking is critical for neurons’ survival and functions including synaptic
neurotransmission. However, mitochondrial trafficking and dynamics in mutant LRRK2
associated-PD has not been well studied. We find that the mitochondrial oxidant stress is
elevated in the LRRK2-R1441G mutants whereas mitochondrial respiration and mitochondrial
ATP synthesis is significantly reduced. In addition, our preliminary studies uncovered early and
defining features in mitochondria trafficking and dynamics impairment: frangmented
mitochondria in SNc dopamine neurons and terminals, increased cytosolic calcum levels, tau
hyperphosphorylation, and decreased anterograde healthy mitochondrial transport. We
hypothesize that R1441G mutation impairs mitochondria trafficking and dynamics via
dysregulation of Miro1 and calcium homeostasis and pathologic tau accumulation that ultimately
result in synaptic dysfunction, energy failure and axonal degeneration. We will utilize a
combination of two-photon imaging (2PLSM) and electrophysiology recording in living brain
slices, and mouse genetics to uncover mechanisms underlying DAergic transmission deficits
and axonal degeneration in PD.

## Key facts

- **NIH application ID:** 10891269
- **Project number:** 7R01NS128005-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** HUI ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $437,429
- **Award type:** 7
- **Project period:** 2022-06-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891269

## Citation

> US National Institutes of Health, RePORTER application 10891269, Synaptic Dysfunction and Energy Failure in Parkinson's Disease (7R01NS128005-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10891269. Licensed CC0.

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