Mutations in LRRK2 are a common genetic cause of Parkinson's disease (PD). Diseases associated with LRRK2 are associated with both alpha-synuclein pathology and with tau pathology. The association of LRRK2 with multiple types of pathologies suggests that the biology of LRRK2 could provide particular insight to our understanding of mechanisms of neurodegeneration. Our studies suggest that LRRK2 modifies cellular responses to stress. Expressing wild type LRRK2 confers to C. elegans striking sensitization to stresses associated with increased protein misfolding and protection against mitochondrial toxins, such as rotenone and paraquat. Knockdown of lrk-1, the C. elegans homologue of LRRK2, has the opposite effects and renders C. elegans less vulnerable to proteasomal inhibition and more vulnerable to rotenone. C. elegans expressing PD-associated LRRK2 mutants show more toxicity than seen with wild type LRRK2. These observations are supported by protein-binding studies in human cell lines and suggest that the action of LRRK2 requires the protein folding machinery and the stress kinase cascade. The knockdown and binding studies show evidence of functional and physical interactions with identification of several binding proteins including CHIP, MKK3, 6 and 7, and JIP2 &4, as well as functional links to hsp60 and 70. The interaction between LRRK2 and MKK6 appears to be particularly important in the pathophysiology of PD because the PD-related mutations in LRRK2 show increased binding that is selective for MKK6. Many of these binding proteins share a common function in that they mediate different elements of the cellular stress response. We hypothesize that LRRK2 coordinates the cellular stress response through its interaction with proteins linked to the protein misfolding pathways and the stress kinase cascades. A secondary element of this hypothesis is that mutations in LRRK2 associated with PD enhance cell death and neurodegeneration by increasing signaling through the stress kinase cascades.
The first aim will investigate how LRRK2 modifies the response to cell injury.
This aim will also examine how knockdown of LRRK2 binding proteins modifies the actions of LRRK2 in C. elegans lines and LRRK2 inducible human cell lines.
The second aim will determine the structural mechanisms by which LRRK2 interacts with its binding proteins.
The third aim examines how expression of wild type, G2019S and R1441C LRRK2 modify toxicity and inclusion formation caused by genetic changes related to PD (alpha-synuclein and tau) in C. elegans.
This aim will elucidate whether wild type LRRK2 normally protects against pathophysiological changes associated with PD, and whether PD-related mutations in LRRK2 enhance these changes.

Public Health Relevance

Parkinson's disease (PD) is the most common degenerative movement disorder. Mutations in LRRK2 are the most common genetic cause of PD identified to date with mutations in LRRK2 account for up to 40% of familial PD in some populations. This proposal will elucidate the mechanism of action of LRRK2, which could pave the way for new therapeutic approaches to this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060872-04
Application #
8214525
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sieber, Beth-Anne
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$348,359
Indirect Cost
$133,984
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Boyd, Justin D; Lee-Armandt, J Peter; Feiler, Marisa S et al. (2014) A high-content screen identifies novel compounds that inhibit stress-induced TDP-43 cellular aggregation and associated cytotoxicity. J Biomol Screen 19:44-56
Saha, Shamol; Liu-Yesucevitz, Liqun; Wolozin, Benjamin (2014) Regulation of autophagy by LRRK2 in Caenorhabditis elegans. Neurodegener Dis 13:110-3
Dusonchet, Julien; Li, Hu; Guillily, Maria et al. (2014) A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity. Hum Mol Genet 23:4887-905
Liu-Yesucevitz, Liqun; Lin, Amy Y; Ebata, Atsushi et al. (2014) ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34:4167-74
Ravid, Katya; Wolozin, Benjamin (2013) The Scientist's Pledge. Acad Med 88:743
Vanderweyde, Tara; Youmans, Katie; Liu-Yesucevitz, Liqun et al. (2013) Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review. Gerontology 59:524-33
Ferree, Andrew; Guillily, Maria; Li, Hu et al. (2012) Regulation of physiologic actions of LRRK2: focus on autophagy. Neurodegener Dis 10:238-41
Wolozin, Benjamin; Gabel, Christopher; Ferree, Andrew et al. (2011) Watching worms whither: modeling neurodegeneration in C. elegans. Prog Mol Biol Transl Sci 100:499-514
Chan, Diane; Citro, Allison; Cordy, Joanna M et al. (2011) Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem 286:16140-9
Liu-Yesucevitz, Liqun; Bassell, Gary J; Gitler, Aaron D et al. (2011) Local RNA translation at the synapse and in disease. J Neurosci 31:16086-93

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