# Exercise and pharmacological LRRK2 inhibition for preventing PD

> **NIH VA IK2** · VA NEW JERSEY HEALTH CARE SYSTEM · 2020 · —

## Abstract

Mild Traumatic Brain Injury (mTBI) results in a 56% higher risk of developing Parkinson’s disease (PD) in U.S.
Veterans. PD presents clinically with resting tremors, balance problems, gait instability, and locomotor deficits.
Histological hallmarks of PD are spread of alpha synuclein (α-syn) pathology through interconnected brain
regions, and selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). There is no
cure for PD and treatments are only palliative. With OEF/OIF Veterans entering middle-age, when the diagnosis
of PD becomes more prevalent, it is important to identify factors and events that increase the risk of potentially
developing PD and, more importantly, potential mitigating factors that slow its progression. Exercise has been
shown to prevent age-related brain deterioration and is associated with better white matter fiber integrity
resulting in improved executive function in patients with mild cognitive impairment. Environmental enrichment
in animals and rehabilitation including physiotherapy in patients, have been shown to significantly improve
recovery and decrease hospital stay in patients with TBI. However, the effectiveness of exercise at preventing
PD during rehabilitation from mTBI is unknown. Genome wide association studies have linked mutations in
Leucine Rich Repeat Kinase-2 to late onset PD that is pathologically indistinguishable from idiopathic PD. These
findings suggest that LRRK2 likely also plays a role in non-genetic causes of PD. Recent in vitro and in vivo
studies show that inhibition of kinase activity in WT-LRRK2 or gain-of-function LRRK2 mutants, confers robust
neuroprotection in models of neuroinflammation and PD. To date, all pharmacological treatments aimed at
preventing or stopping PD progression have failed in human clinical trials and this may be due to preclinical
studies that relied primarily on incomplete PD animal models. In spite of best efforts, use of these incomplete
PD models, (e.g. neurotoxin induced lesions in brain areas affected in PD without accompanying α-syn
pathology) has also failed to produce a bonafide biological link between mTBI and PD. This lack of clarity is
likely why no effective rehabilitation methods or treatments to stop or prevent PD currently exist. Injection of
amyloidogenic pre-formed α-syn fibrils (PFF) into the SNpc of rodents causes formation and spread of human-
like α-syn pathology through the interconnected brain regions, progressive and selective dopaminergic
neurodegeneration with PD related behavioral deficits. Using this more complete model of late onset PD, we
plan to determine the connection between mTBI and PD and to test potential treatments that may prevent PD.
Our overall hypothesis is that repetitive mTBI (r-mTBI) promotes PD pathology in vulnerable individuals (i.e.
those with undetected PD), but exercise combined with new pharmacotherapies can delay the progression of
PD, even in vulnerable individuals. We will test our hypoth...

## Key facts

- **NIH application ID:** 10069647
- **Project number:** 1IK2RX003253-01A2
- **Recipient organization:** VA NEW JERSEY HEALTH CARE SYSTEM
- **Principal Investigator:** Vedad Delic
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069647

## Citation

> US National Institutes of Health, RePORTER application 10069647, Exercise and pharmacological LRRK2 inhibition for preventing PD (1IK2RX003253-01A2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10069647. Licensed CC0.

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