Parkinson disease (PD) is an age-associated multi-factorial disorder resulting from a combination of genetic and environmental factors. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of autosomal dominant Parkinsonism. In some populations, the frequency of LRRK2 mutations accounts for as much as 30% of familial PD cases, with G2019S being the most frequent mutation. LRRK2 mutations are also found in some sporadic Parkinsonism patients. Four years have passed since the first mutations in LRRK2 were identified, but the function of Lrrk2 and how mutations lead to PD remains largely unknown. To gain insight into the pathologic mechanisms of the mutations, we have created LRRK2 knock-out and Lrrk2 G2019S knock-in mouse models. These models represent excellent physiological test systems to evaluate the normal and physiological roles of Lrrk2. We will characterize these mice for neuronal vulnerability, neurodegenerative alterations, dopamine release and behavioral alterations, phenotypes that have all been linked to Lrrk2 function. This work should significantly contribute to our understanding of the functional role of Lrrk2 and direct future studies and therapeutic design.

Public Health Relevance

Mutations in the gene LRRK2 cause Parkinson Disease. This proposal aims to use animal models to study the biological manner in which LRRK2 mutations exert their pathogenic effects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic Jacksonville
United States
Zip Code
Volta, Mattia; Melrose, Heather (2017) LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis. Biochem Soc Trans 45:113-122
Melrose, Heather L (2015) LRRK2 and ubiquitination: implications for kinase inhibitor therapy. Biochem J 470:e21-4
Yue, M; Hinkle, K M; Davies, P et al. (2015) Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol Dis 78:172-95
West, Andrew B; Cowell, Rita M; Daher, João P L et al. (2014) Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 522:2465-80
Bailey, Rachel M; Covy, Jason P; Melrose, Heather L et al. (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol 126:809-27
Davies, Paul; Hinkle, Kelly M; Sukar, Nour N et al. (2013) Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies. Biochem J 453:101-13
Hinkle, Kelly M; Yue, Mei; Behrouz, Bahareh et al. (2012) LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol Neurodegener 7:25
Dächsel, Justus C; Behrouz, Bahareh; Yue, Mei et al. (2010) A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat Disord 16:650-5