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

By E. Greggio, S. Jain, A. Kingsbury, R. Bandopadhyay, P. Lewis, Alice Kaganovich, M. P. van der Brug, A. Beilina, J. Blackinton, K. J. Thomas and 8 more. Neurobiology of Disease, 2006

750 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/020ed0546890d182f496145c514dc9b2e66f6c37

How researchers see this paper

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In Cellular and Molecular Neuroscience

1. H. Ko
2. Valina L. Dawson
3. T. Dawson
4. Christian Haass

In Neurology

1. H. Ko
2. Valina L. Dawson
3. T. Dawson
4. A. Lutz
5. Christian Haass
6. K. Winklhofer
7. Nicole Exner
8. Mark P. Mattson

Citations in the corpus

• Genetic Animal Models of Parkinson’s Disease (2010, positive): “In cellular models, overexpression of disease-causing mutations of LRRK2 are toxic, and the toxicity is kinase and GTP-binding dependent (Greggio et al., 2006; Smith et al., 2006; West et al., 2007b).”
• Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. (2007, background): “Besides large in vitro assays that biochemically characterize LRRK2 protein, a number of previous studies have applied exogenous LRRK2 expression to various cell systems (17,18).”
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “Overexpression of pathogenic LRRK2 mutants in cultured cells, primary neurons or rodents causes cellular toxicity, which is dependent on the kinase activity (Greggio et al , 2006; Smith et al , 2006; West et al , 2007; Ho et al , 2009; Dusonchet et al , 2011).”