Project 3: LRRK2 Biology in Parkinson's Disease Parkinson's disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. It is currently thought that PD results from a combination of environmental factors and genetic susceptibility. Gene mutations in the leucine-rich repeat kinase 2 (LRRK2) have recently been shown to result in autosomal dominant PD. A high prevalence of these mutations in unrelated PD patients strongly suggests that mutant LRRK2 may play a key role in sporadic PD as well. The clinical and pathological phenotypes of LRRK2 PD patients are similar to classic late-onset PD, further emphasizing the potential importance of this gene. Biochemical evidence suggests that aberrant GTPase and kinase activities are linked to disease causing mutations, and may be at the basis of neuronal toxicity and pathogenesis of PD. The cell biology and pathobiological actions of LRRK2 are not yet known. To understand the role of LRRK2 in the function and dysfunction of neurons we have generated LRRK2 knockout mice and LRRK2 transgenic mice. With Cores B, C and D, we will study the neurochemical, neuroanatomical and behavioral changes in these mice as they age. We will explore the effects of oxidative stress in genetically engineered LRRK2 mice to examine the interplay of genetics and environmental effects on neuropathology. Since increased activity of LRRK2 is associated with neurotoxicity we will explore the cellular regulation of LRRK2 expression by the E3 ubiquitin ligase CHIP and its effects on neuronal viability. We expect that LRRK2 functions in large protein complexes and thus we propose to identify and characterize LRRK2 interacting proteins. The goals of this project are to identify and characterize the interaction of LRRK2 and its protein targets with the hope that these studies of LRRK2 may potentially lead to the development of novel therapeutic strategies for the treatment of PD.

Public Health Relevance

Gene mutations in LRRK2 are a common cause of familial and perhaps sporadic PD, yet little is know about how this protein functions, what cellular signaling networks it plays a role in and how mutations cause PD. The goals of this project are to understand the biology of LRRK2 to learn about the pathogenesis familial and sporadic PD and to identify potential new targets for future drug development to treat PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038377-15
Application #
8533018
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2013
Total Cost
$341,619
Indirect Cost
$133,315
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106
Mao, Xiaobo; Ou, Michael Tianhao; Karuppagounder, Senthilkumar S et al. (2016) Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353:
Geiger, Joshua T; Arthur, Karissa C; Dawson, Ted M et al. (2016) C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies. Neurodegener Dis 16:370-2
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23
Jo, Junghyun; Xiao, Yixin; Sun, Alfred Xuyang et al. (2016) Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell 19:248-57
Karuppagounder, Senthilkumar S; Xiong, Yulan; Lee, Yunjong et al. (2016) LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. J Chem Neuroanat 76:90-97
Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224
Nucifora Jr, Frederick C; Nucifora, Leslie G; Ng, Chee-Hoe et al. (2016) Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat Commun 7:11792
Mills, Kelly A; Mari, Zoltan; Pontone, Gregory M et al. (2016) Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes. Parkinsonism Relat Disord 33:107-114

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