# LRRK2-mediated molecular and synaptic events in the striatum

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $387,060

## Abstract

Project Summary
Parkinson's disease (PD) is the second most common neurodegenerative disease of aging. Mutations in
LRRK2 are associated with both inherited and sporadic forms of PD. LRRK2 is highly enriched in spiny
projection neurons (SPN) in the dorsal striatum. However, the physiological role of LRRK2 in SPNs remains
elusive. Our previous observations suggest a linkage between the pathogenic R1441C mutation and aberrant
PKA signaling in SPNs. However, the analyses were limited by the inherent resolution provided by
conventional biochemical approaches and microscopy. In this proposal, we seek to provide more precise
information about the pathophysiological consequences of LRRK2 mutations in SPNs. In particular, it is our
central hypothesis that LRRK2R1441C mutation leads to aberrant dopaminergic signaling in SPNs. The resultant
striatal dysfunction, in turn, contributes to the symptomatology of PD. To pursue this, we will examine if
LRRK2R1441C mutation alters dopamine signaling, corticostriatal transmission, corticostriatal plasticity, and
excitability in SPNs through PKA signaling dysregulation. Moreover, assessment of striatal-dependent motor
learning along with pharmacological manipulations will provide insight on the effects of LRRK2R1441C mutation
in a whole-animal setting. In conjunction with standard cellular, molecular, and electrophysiological
approaches, our investigations will capitalize on a combination of cutting-edge approaches that overcome
obstacles that have impeded progress to date. These include, LRRK2 mutant mice, striatal pathway-specific
(Cre and reporter) mice, viral gene delivery, and super-resolution imaging. The successful achievement of
these aims will significantly advance our understanding of the mechanisms underlying PD, and in doing so, will
promote the development of new therapies for PD patients in the future.

## Key facts

- **NIH application ID:** 9975929
- **Project number:** 5R01NS097901-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Loukia Parisiadou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,060
- **Award type:** 5
- **Project period:** 2016-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975929

## Citation

> US National Institutes of Health, RePORTER application 9975929, LRRK2-mediated molecular and synaptic events in the striatum (5R01NS097901-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9975929. Licensed CC0.

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