In the period covered by this report, we have followed two major pieces of our work on the molecular and cell biology of inherited Parkinson disease (PD).? ? The first major piece of work is a continuation of previous studies examining the functions of proteins related to recessive parkinsonism. In collaboration with Tim Greenamyre at Pittsburgh, we have shown that DJ-1 reacts to chronic oxidative stress in vivo, modeled by application of the mitochondrial complex I inhibitor, rotenone. We have also shown that the ability of DJ-1 to protect cells in culture against rotenone toxicity depends on this ability to oxidize. In further work, which we are following up at the moment, we have started to explore the possibility that DJ-1 has RNA binding activity, linking oxidation to control of gene expression. Mutations in PINK1, a mitochondrial kinase, cause similar phenotypes in humans and therefore one might imagine DJ-1 and PINK1 having related functions. We have therefore also screened for potential substrates for PINK1 and are currently validating their involvement in neuronal damage.? ? The second project revolves around the gene LRRK2, cloned in 2004 by NIA researchers, associated with autosomal dominant Parkinson disease. LRRK2 encodes a large protein, dardarin, which has several domains including a kinase domain where some mutations have been found. Our initial studies have focused on the kinase domain and we have shown that a fully active version of the kinase domain is required for the full expression of the toxic effects of mutant LRRK2 in cell culture models. This has important implications for drug development as it shows that finding ways to inhibit the kinase domain may lead to novel treatments. We have also begun studies of how the protein is activated by signal transduction networks in the cell. Our long-term intention is to establish whether LRRK2 is a valid target for therapeutic intervention.
| Bisaglia, Marco; Greggio, Elisa; Maric, Dragan et al. (2010) Alpha-synuclein overexpression increases dopamine toxicity in BE2-M17 cells. BMC Neurosci 11:41 |
| Dehvari, Nodi; Sandebring, Anna; Flores-Morales, Amilcar et al. (2009) Parkin-mediated ubiquitination regulates phospholipase C-gamma1. J Cell Mol Med 13:3061-8 |
| Saha, Shamol; Guillily, Maria D; Ferree, Andrew et al. (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 29:9210-8 |
| van der Brug, Marcel P; Blackinton, Jeff; Chandran, Jayanth et al. (2008) RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc Natl Acad Sci U S A 105:10244-9 |
| Cookson, Mark R; van der Brug, Marcel (2008) Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp Neurol 209:5-11 |
| Mortiboys, Heather; Thomas, Kelly Jean; Koopman, Werner J H et al. (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64:555-65 |
| Greggio, Elisa; Lewis, Patrick A; van der Brug, Marcel P et al. (2007) Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1. J Neurochem 102:93-102 |
| van de Leemput, Joyce; Chandran, Jayanth; Knight, Melanie A et al. (2007) Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 3:e108 |
| Lewis, Patrick A; Greggio, Elisa; Beilina, Alexandra et al. (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 357:668-71 |
| Betarbet, Ranjita; Canet-Aviles, Rosa M; Sherer, Todd B et al. (2006) Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system. Neurobiol Dis 22:404-20 |
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