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).? ? We have continued to examine how mutations in recessive genes leading to parkinsonism, DJ-1 and PINK1, cause cell death. In work that has recently been submitted for publication, we have identified an oxidative-stress responsive RNA binding activity for DJ-1, a protein that has so far had no characterized function. Our work shows that several aspects of the function of this protein, in maintaining mitochondrial viability, modulating cell survival pathways and maintaining antioxidant status are most readily explained byt the single biochemical activity of RNA binding. We have also explored how mutations in a mitochondrial kinase, PINK1, affect mitochondrial morphology and function in living cells, again under oxidative conditions.? ? Most of our work over the past year has been aimed at expanding our previously published studies showing that a dominant gene for Parkinson's disease, LRRK2, is toxic to neurons when mutated. We had shown that some mutations in LRRK2 trigger cell death by virtue of increased kinase activity. However, we also found that some mutations outside of the kinase domain are equally toxic and trigger cell death in a kinase-dependent manner without apparently increasing kinase activity in vitro. In the past year we have shown that these mutations work by slowing GTPase activity of the protein in complex, which will leave the kinase in a higher activity state for longer than the wild type protein. We have also shown that the mutations cannot be placed into a related kinase, LRRK1, and cause the same toxic effect. Our aggregate data clearly support the hypothesis that kinase activity is a promising therapeutic target for Parkinson's disease.
| Bisaglia, Marco; Greggio, Elisa; Maric, Dragan et al. (2010) Alpha-synuclein overexpression increases dopamine toxicity in BE2-M17 cells. BMC Neurosci 11:41 |
| Saha, Shamol; Guillily, Maria D; Ferree, Andrew et al. (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 29:9210-8 |
| Dehvari, Nodi; Sandebring, Anna; Flores-Morales, Amilcar et al. (2009) Parkin-mediated ubiquitination regulates phospholipase C-gamma1. J Cell Mol Med 13:3061-8 |
| 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 |
| 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 |
| 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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