# Targeting proteostatic mechanisms to inhibit LRRK2-mediated neurodegeneration and neuropathology

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $780,220

## Abstract

Neurodegenerative dementias, such as Alzheimer's disease (AD), frontotemporal lobar
degeneration, and Lewy body dementia, are caused by abnormalities in proteostasis and
accumulation of misfolded prion-like proteins in the brain. Mutations in the Leucine-rich repeat
kinase 2 (LRRK2) gene result in diverse neuropathology, including tauopathy, synucleinopathy,
TDP-43 proteinopathy, and AD pathology. Patients with LRRK2 mutations frequently develop
clinical dementia, and nearly half of patients with LRRK2-driven neurodegeneration develop tau
or other pathology instead of synucleinopathy. LRRK2 is therefore a key regulator controlling
protein aggregation and neurodegeneration, and defining the mechanisms by which LRRK2
mutations drive such varied prion-like pathology may lead to novel targeted therapeutics. The
proposed study aims to characterize the proteostatic mechanisms upstream and downstream of
LRRK2 using patient-derived neurons and rare postmortem LRRK2 patient brain tissue. The
study has three goals. First, to define the role of LRRK2’s subcellular localization in its cellular
functions and degradation, with a particular focus on LRRK2 microtubule association and
endolysosomal activation. Second, to test the extent to which newly identified LRRK2 protein
degradation pathways rescue neurotoxicity in patient-derived aged neurons and other disease
relevant systems. Third, to define the mechanisms by which LRRK2 mutations can drive both
synucleinopathy and tauopathy using real-time quaking-induced conversion (RT-QuIC), detailed
neuropathology, and cell-type specific transcriptomics on a rare cohort of LRRK2 patient brain
tissues. Overall, these studies should begin to define the mechanisms by which LRRK2 drives
myriad neuropathology and provide insight into the relevance of LRRK2 as a therapeutic target
for tauopathies.

## Key facts

- **NIH application ID:** 11081475
- **Project number:** 7R01NS135607-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Annie E Hiniker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,220
- **Award type:** 7
- **Project period:** 2024-04-30 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11081475

## Citation

> US National Institutes of Health, RePORTER application 11081475, Targeting proteostatic mechanisms to inhibit LRRK2-mediated neurodegeneration and neuropathology (7R01NS135607-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11081475. Licensed CC0.

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