Genetic forms of neurodegenerative disorders can help us to define the pathways associated with cellular dysfunction and damage. We are currently using dominant mutations to model cellular damage in Parkinson's disease (PD), dystonia and amyotrophic lateral sclerosis (ALS). Increasingly, we are also focusing on recessive genes that produce overlapping phenotypes to the dominant mutations. The concept is to understand the molecular links between different genes that cause the same disease, and thus to delineate the pathways that underlie neuronal dysfunction and cell death. In PD, where most of the work has been focused, we have shown that mutant alpha-synuclein causes neuronal death and that there is selectivity in these effects. Neurons that use express a dopaminergic neurotransmitter are selectively vulnerable to mutant alpha-synuclein, at least within the cell population cultured from the midbrain. Furthermore, we found that the recessive gene product Parkin can reverse this damage and we have implicated the ubiquitin-proteasome system in this relationship. Using gene-expression profiling, we have identified neurotransmitter alterations in aalpha-synuclein cell lines. We have also collaborated on a number of studies where new PD mutations have been identified, for example in the alpha-synuclein binding protein synphilin-1. More recently, we have begun working on an additional recently discovered recessive PD gene, DJ-1. We have already identified how a point mutation in DJ-1 causes disease; by altering conformation of an alpha-helix near the C-terminus, the protein is greatly destabilized. The challenge now is to understand the cellular function of the normal DJ-1 protein and develop models for loss of this function within the nervous system. Furthermore, whether DJ-1 has any interactions with parkin or alpha-synuclein is under investigation. Work on other diseases has also continued. Some observations of gene expression changes caused by dominant TorsinA mutations have been published, and more extensive work on these mutations is in preparation. We have shown that a recently reported mutation in TorsinA does not have the same cellular effects as a more common, previously reported deletion and have shown that the heat shock protein system is affected by expression of torsinA in vitro. Work on ALS has continued with a proteomics analysis of SOD1 mutations now published; we are currently applying similar approaches to PD models.
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| 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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