Leucine rich repeat kinase 2 (LRRK2) mutations are causal for inherited Parkinsons disease with age-dependent penetrance. The protein is a large complex kinase with several reported protein interactions and mutliple proposed functions. Some mutations increase kinase activity, and the overall aim of this project is to extend our prior observations that kinase activity of LRRK2 is important in pathogenesis association with mutations in this gene. Our current work includes examination of the effects of mutations both inside and outside of the kinase domain on kinase activity. It has been suggested that GTP binding to the ROC domain of LRRK2 increases kinase activity. However, we have found instead that this is likely not a direct effect of binding of the guanosine nucleotide to the ROC domain. However, mutations in LRRK2 in the ROC domain that completely abolish the capacity to bind guanosine nucleotides do decrease kinase activity, suggesting that there may be structural effects of modulating this region. We are currently following this data up by examining other mutations outside of the kinase domain that have similar effects of limiting kinase activity. We have combined our interest in gene expression with models of LRRK2 mutation, particularly focusing on mutations in the kinase domain. It has been suggested that LRRK2 may modulate gene expression in a number of ways, including by interaction with microRNA processing enzymes. This would predict that LRRK2 would have strong effects on gene expression. However, we did not find evidence to support this idea in transfected cell lines, in fibroblasts from LRRK2 patients or from brain regions where LRRK2 is expressed taken at ages where pathology was established in other parts of the brain. Overall, these data suggest that if LRRK2 influences gene expression it is likely by indirect mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000948-04
Application #
8335982
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$544,654
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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