# PATHOLOGIC LRRK2 SIGNALING IN FAMILIAL AND IDIOPATHIC PARKINSON'S DISEASE

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $351,213

## Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. While the causes of
PD are not fully known, the rare familial forms of the disease continue to provide valuable insight into pathways
that contribute to disease. For example, alpha-synuclein was discovered to be the major protein component of
Lewy bodies only after the gene encoding it was linked to familial PD.
 Autosomal dominant mutations in LRRK2 are the most frequent genetic cause of PD, with patients
most commonly presenting with late onset and classic Lewy body/synuclein pathology. We recently reported
that endogenous expression of G2019S LRRK2, the most frequent pathogenic mutation, induces lysosomal
abnormalities and the accumulation of insoluble synuclein in neurons. Notably, these effects were reversed by
LRRK2 kinase inhibitors. However, the LRRK2 substrates that are aberrantly phosphorylated by G2019S
LRRK2 to produce these defects, and whether these changes represent a final common pathologic pathway
for all LRRK2 mutations and idiopathic PD, is not known.
 A subset of the Rab family of small GTPases are now recognized as physiological substrates of LRRK2
kinase activity. Rabs are critically involved in intracellular trafficking and exert powerful influence on the
function of many organelles, including lysosomes. We have focused our attention here on Rab8a as a critical
intermediary in PD pathogenesis. Rab8a is not only a substrate of LRRK2, but has been linked to other familial
and idiopathic forms of PD. While all PD mutations appear to increase Rab phosphorylation, the R1441C
mutation in LRRK2 possesses far greater Rab-kinase activity than G2019S. This could translate to greater
neuronal dysfunction but has not be adequately addressed. Given the PD-relevant outcomes we recently
established for G2019S LRRK2, we will determine here whether the R1441C mutation exerts greater defects in
lysosome function and synuclein metabolism using both mouse primary neurons and human iPSC-derived
neurons. We will then examine the relative effects of G2019S and R1441C LRRK2 on Rab8a biochemistry and
biology, and dissect the precise role of Rab8a in LRRK2-mediated neuronal pathology. Lastly, we will
investigate whether dysregulation of LRRK2 signaling pathways contribute to idiopathic PD. Through a careful
analysis of post mortem brain tissue from idiopathic PD patients and age-matched controls, we will interrogate
the status of multiple upstream and downstream features of LRRK2 protein and markers of LRRK2 kinase
activity. We have assembled a team with deep expertise in cell biology and neuropathology and will complete a
series of critical and timely experiments to provide much-needed insight into the mechanistic and pathogenic
consequences of disease-linked LRRK2 mutations in neurons, and whether these pathways are involved in the
far more common idiopathic cases of PD.

## Key facts

- **NIH application ID:** 10241552
- **Project number:** 5R01NS110188-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Matthew J Lavoie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,213
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241552

## Citation

> US National Institutes of Health, RePORTER application 10241552, PATHOLOGIC LRRK2 SIGNALING IN FAMILIAL AND IDIOPATHIC PARKINSON'S DISEASE (5R01NS110188-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241552. Licensed CC0.

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