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Kinase activity is required for the toxic effects of mutant LRRK2/dardarin

Greggio, Elisa, Jain, Shushant, Kingsbury, Ann, Bandopadhyay, Rina, Lewis, Patrick, Kaganovich, Alice, van der Brug, Marcel P., Beilina, Alexandra, Blackinton, Jeff, Thomas, Kelly Jean, Ahmad, Rili, Miller, David W., Kesavapany, Sashi, Singleton, Andrew, Lees, Andrew, Harvey, Robert J., Harvey, Kirsten, Cookson, Mark R.·2006·Neurobiology of Disease
DOI 10.1016/j.nbd.2006.04.001
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Abstract

Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Manipulating activity by replacing the kinase domain with a 'kinase-dead' version blocks inclusion body formation and strongly delays cell death. This predicts that kinase inhibitors will be useful therapeutic agents in patients with LRRK2 mutations and, perhaps, in sporadic PD. We also show that dardarin protein is expressed within human midbrain neurons and that C-terminal epitopes are also found in some Lewy bodies.

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Research works printed but not linked: 27

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Metadata

Authors
Greggio, E., Jain, S., Kingsbury, A., Bandopadhyay, R., Lewis, P., Kaganovich, A., van der Brug, M. P., Beilina, A., Blackinton, J., Thomas, K. J., Ahmad, R., Miller, D. W., Kesavapany, S., Singleton, A., Lees, A., Harvey, R. J., Harvey, K., & Cookson, M. R.
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2006-08
Volume
23
Issue
2
Pages
329-341
ISSN
0969-9961
DOI
10.1016/j.nbd.2006.04.001
Cited by
671
References
1
Language
en
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