All ETDs from UAB

Advisory Committee Chair

Andrew B West

Advisory Committee Members

Matthew Goldberg

Jeremy Herskowitz

Mark Suto

Shaida Andrabi

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Parkinson’s disease (PD) is an age-related, progressive, movement disorder pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous aggregates, termed Lewy bodies, that are largely comprised of αSynuclein (αSyn). Missense mutations in the leucine-rich repeat kinase (LRRK2) gene are the most common genetic cause of PD and lead to gain-of-function increases in kinase activity. The G2019S-LRRK2 mutation is the most frequent mutation and elevates kinase activity by ~2-3 fold. Genetic and biochemical evidence suggest elevated LRRK2 kinase activity plays a pathogenic role in the development of PD, implicating LRRK2 as a valid drug target for disease modification. This thesis combines LRRK2 small molecule tool compounds with animal models of disease to characterize pharmacodynamic markers of LRRK2 kinase inhibition, test efficacy for neuroprotection, and evaluate LRRK2 target engagement biomarkers in biofluids as a means to predict potential outcomes and pitfalls in early phase clinical trials of LRRK2-targeted therapeutics. We find that there is reduced potency for blocking G2019S-LRRK2 kinase activity and that G2019S-LRRK2 expression protects from inhibitor-induced phenotypes in the periphery. Additionally, exogenous αSyn pre-formed fibrils (PFFs) induce the formation of toxic αSyn inclusions and neurodegeneration similarly in G2019S-LRRK2 and non-transgenic rodents, but only G2019S-LRRK2 expressing rats experience moderate protection of dopaminergic neurons in the SNpc with prophylactic LRRK2 kinase inhibitor treatment. Lastly, we characterize pharmacodynamic measures of LRRK2 kinase inhibition in biofluids procured from non-human primates to explore relationships between cellular and extracellular LRRK2. Collectively these findings suggest that the utility of LRRK2 kinase inhibitors for treating PD may be best suited for individuals demonstrating elevated LRRK2 kinase levels, and that that implementation of LRRK2 biomarkers is likely to improve PD clinical trial outcomes.

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