# Role of LRRK2 in idiopathic Parkinson's disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $342,344

## Abstract

Mutations in LRRK2 cause familial Parkinson disease (PD) and, in some populations, may account for up to 40% of all
cases3. The LRRK2 gene locus also contains a risk factor for `idiopathic' PD (iPD); however, the role of LRRK2 in
typical iPD is not clear. Furthermore, the relationship of LRRK2 to other genes and proteins associated with PD, such as
α-synuclein, is also relatively unexplored. While the mechanism(s) by which mutant LRRK2 causes neurodegeneration
are not entirely certain, it is generally believed that disease-causing mutations may be associated with increased kinase
activity, at least in situ in intact cells. However, a critical barrier to understanding the role of endogenous, wildtype
LRRK2 in iPD is the absence of a practical, high-resolution assay for its activation state.
We have developed and validated a pair of novel proximity ligation assays with excellent anatomical resolution that can
rapidly provide information regarding activation state, cellular localization and physiological regulators of LRRK2. The
assay is based on (i) S1292 phosphorylation and (ii) dissociation of 14-3-3 from LRRK2. Using this and other assays, we
have preliminary evidence that (i) LRRK2 is activated in nigrostriatal neurons in iPD; (ii) sublethal concentrations of
rotenone activate LRRK2; (iii) overexpression of α-synuclein in vivo activates LRRK2 in nigrostriatal neurons; (iv)
LRRK2 activation is mediated by oxidative mechanisms. We now propose to examine the role of LRRK2 in iPD and its
potential physiological interactions with α-synuclein and mitochondria. We will investigate the following questions: (1)
What is the activation state of LRRK2 in human iPD brain tissue? (2) To what extent can endogenous LRRK2 activation
be modeled in the rotenone rat? (3) Does!α-synuclein activate endogenous WT LRRK2? (4) Does oxidative stress activate
LRRK2?

## Key facts

- **NIH application ID:** 9952437
- **Project number:** 5R01NS100744-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** J Timothy Greenamyre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,344
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952437

## Citation

> US National Institutes of Health, RePORTER application 9952437, Role of LRRK2 in idiopathic Parkinson's disease (5R01NS100744-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9952437. Licensed CC0.

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