Research in the cell biology and gene expression section of LNG aims to use cellular and molecular biology to understand the functions of genes associated with neurodegeneration. In the last year, we have mainly focused on DJ-1, a recessive gene associated with parkinsonism. DJ-1 is part of a large superfamily of genes across different species whose members have variable functions including chaperones and proteases. Eukaryotic DJ-1 orthologs form a distinct grouping separate from known members of the superfamily, suggesting a function for these gene products that may be distinct from other known members. We, and others, have shown that the L166P mutation in DJ-1 produce disease due to destabilization of the protein. This has been followed up by a more extensive survey of all known mutations and polymorphisms, where we have seen that one additional mutation (M26I) is also unstable, although the effect is smaller than for L166P. In the initial reports of DJ-1 association with recessive parkinsonism, it was suggested that mutations cause the protein to be associated with mitochondria. However, we found that a small proportion of DJ-1 is normally associated with mitochondria, suggesting that this is not a mutation-specific effect. Instead, we have suggested that association with mitochondria is promoted by oxidative conditions and this helps to protect cells against toxins that damage mitochondrial complex I activity. This association is controlled by modification of a specific cysteine, as artificial mutations where this residue is mutated are deficient in both mitochondrial localization and neuroprotective ability. This modification also correlates with the acidification of the protein. It is likely that formation of cysteine-sulfinic acids is also found in vivo, as analysis of samples from Parkinson?s disease brains show similar acidic shifts of endogenous DJ-1. There are several observations pointing to a possible role of recessive mutations in the control of cell viability after mitochondrial damage, which have been summarized recently. Although DJ-1 has been a major focus, we have also continued to work on other genes associated with recessive parkinsonism. For example, we have shown that some mutations in parkin, a protein-ubiquitin ligase, can promote accumulation into aggresomes in the cytosol of neurons. The physiological relevance of this observation is unclear, but suggests that some parkin mutants are liable to become misfolded unless cleared by the cell. A third gene for recessive parkinsonism, PINK1, has been described. This is a serine/threonine directed protein kinase whose substrates are not yet known but is predicted to be localized to mitochondria. Like DJ-1, PINK1 has been reported to protect neurons against cellular stress, a hypothesis that we will be investigating. Several mutations in alpha-synuclein, including a triplication of the wild-type allele, are associated with dominantly inherited form of PD/Lewy body disease. In collaboration with Andrew Singleton, LNG, we have shown that this protein aggregates in the brain but not in peripheral tissue samples from patients with defined mutations. It has been suspected for several years that aggregation of the protein is related to its toxic effects. This leads to the possibility of designing therapeutic interventions for the disease, by interfering with the process of aggregation. Our collaborators have described small peptides that might perform such a role recently and ongoing research in the laboratory aims at further evaluating these as possible therapeutic agents.
| 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 |
| 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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