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 the following diseases: Parkinson's disease (PD), dystonia and amyotrophic lateral sclerosis (ALS). Our work on PD so far has mainly focussed on the gene alpha-synuclein. We have examined the role of an alpha-synuclein interacting protein, synphilin-1, on the formation of intracellular protein inclusions. Our results indicate that synphilin forms inclusions readily but we did not find a specific recruitment of alpha-synuclein to these inclusions. We also found that this does not trigger cell death. We cloned the mouse homologue of synphilin-1 and found that it was highly conserved. Ongoing work in the lab is aimed at clarifying the role of alpha-synuclein on cell death in dopaminergic neurons, including a collaboration on the accumulation of alpha-synuclein in response to the mitchondrial inhibitor rotenone. We are also working on parkin, a gene associated with recessive forms of PD. We have used a similar approach with mutations in TorsinA, associated with dominant forms of dystonia. Our results show that some mutations form intracellular inclusions, but not all mutations do this, raising the question of distinct mechanisms for different mutations. This work is ongoing, including characterization of a related protein, TorsinB and further work on the mechanism by which mutant TorsinA induces a dominant disorder. Dominant mutations are also found in the motor neuron disorder ALS. Expression of mutant copper/zinc superoxide dismutase (SOD1) produces a variety of effects in cell lines. Work started several years ago has recently been published including the observations that SOD1 mutations (1)alter free radical metabolism (2) produce altered regulation of neurofilament proteins (3) disrupt mitochondrial function and (4) lead to global transcriptional alterations, which can be detected using a microarray approach. We are currently beginning a project to examine whether any similar changes are seen with a recessive gene associated with ALS, alsin.
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| Hardy, John; Cai, Huaiban; Cookson, Mark R et al. (2006) Genetics of Parkinson's disease and parkinsonism. Ann Neurol 60:389-98 |
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