Parkinson disease (PD) is the second most common neurodegenerative disorder. More than 10 million individuals worldwide are expected to have PD by the year 2030, and currently there are no known therapies that slow or halt the relentless progression of the disease. Dominant missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of PD, with up to 40 to 60 thousand carriers of the pathogenic G2019S-LRRK2 mutation in the United States. In individuals of Ashkenazi or Berber descent, frequencies of the G2019S-LRRK2 mutation can be as high as 20-30% in PD patients. In our last project period, we demonstrated that G2019S- LRRK2 expression promotes dopaminergic neurodegeneration caused by ?-synuclein over- expression and that LRRK2 kinase inhibitors blocked these effects. However, the mechanisms linking LRRK2 to ?-synuclein neurotoxicity are not clear. Further dissection of LRRK2 action in PD may expedite the discovery of new therapies that target LRRK2 and related pathways for neuroprotection. We found that LRRK2 is expressed in many neurons tougher with ?-synuclein in healthy brains, but in diseased brains that have ?-synuclein inclusions, LRRK2 is also expressed in myeloid cells that can direct the production of neurotoxic cytokines and reactive-oxygen species. In this competitive renewal request, we hypothesize that LRRK2 expression and kinase activity promotes myeloid cell recruitment to neurons that have ?-synuclein inclusions to exacerbate neurodegeneration and the spread of ?-synuclein inclusions. Using conditional transgenics that inducibly over-express G2019S-LRRK2 in myeloid cells, we will test whether G2019S-LRRK2 can upregulate cytokine responses and oxidative damage caused by neuronal ?-synuclein inclusions through promoting myeloid cell recruitment. Using conditional deletion technology, we will test whether LRRK2 knockout in myeloid cells will downregulate neurotoxic cytokines and oxidative damage in response to ?-synuclein inclusions through inhibiting myeloid cell recruitment. We will explore how LRRK2 protein can control myeloid cell motility and chemotaxis by acting as a novel scaffold for Arp2/3 to control actin polymerization. We predict that LRRK2 interacts with Arp2/3, in a kinase-dependent manner, to facilitate actin microspikes at the leading front of mobile myeloid cells to enhance motility. Completion of these studies should allow for further insight into how LRRK2 can cause PD, how LRRK2 expression in myeloid cells might contribute to neurodegeneration, and definition of a novel actin nucleation complex important for myeloid cell chemotaxis.

Public Health Relevance

Renewal Request for R01-NS064934 'Mechanisms of LRRK2 Neurotoxicity' Parkinson's disease (PD) is the second most common neurodegenerative disorder and a major cause of morbidity and mortality in the United States. The G2019S LRRK2 mutation is the most common known cause of the disease. We will investigate how the G2019S LRRK2 mutation may cause PD and identify new neuroprotective strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS064934-09
Application #
9812140
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sieber, Beth-Anne
Project Start
2018-11-01
Project End
2021-03-31
Budget Start
2018-11-01
Budget End
2019-03-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Liu, Zhiyong; Bryant, Nicole; Kumaran, Ravindran et al. (2018) LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum Mol Genet 27:385-395
Cresto, NoƩmie; Gardier, Camille; Gubinelli, Francesco et al. (2018) The unlikely partnership between LRRK2 and ?-synuclein in Parkinson's disease. Eur J Neurosci :
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Abdelmotilib, Hisham; Maltbie, Tyler; Delic, Vedad et al. (2017) ?-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration. Neurobiol Dis 105:84-98
Zhao, Hien Tran; John, Neena; Delic, Vedad et al. (2017) LRRK2 Antisense Oligonucleotides Ameliorate ?-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids 8:508-519
Gwinn, Katrina; David, Karen K; Swanson-Fischer, Christine et al. (2017) Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program. Biomark Med 11:451-473
Harms, Ashley S; Delic, Vedad; Thome, Aaron D et al. (2017) ?-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration. Acta Neuropathol Commun 5:85

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