Exercise and pharmacological LRRK2 inhibition for preventing PD

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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 hypothesis in the PFF induced model of PD and test if exercise along with pharmacological inhibition of LRRK2 can prevent PD. With highly specific LRRK2 inhibitors entering human trials for treating diagnosed PD, it is essential to determine if together with exercise, this class of drugs can prevent PD in at risk populations. In addition to supporting the scientific objectives, this career development award will provide Dr. Delic with training in different models of brain injury and behavioral as well as neurophysiological outcome measures at the VA New Jersey Health Care System. This training will enable Dr. Delic to successfully translate this and future treatments to the clinic.