Normal Function of Alpha-synuclein
Fully defining the normal functions of alpha-synuclein may help in understanding its role in Parkinson's disease. In the disease, alpha-synuclein forms inclusions, aggregates of abnormally folded protein, that may sequester the protein and prevent it from performing some role that is important under stress conditions, or during aging. One of our approaches to this problem has been a mutagenesis screen in mice, asking for mutations that produce a more severe phenotype in mice that lack alpha-synuclein than in wild type control animals. We have discovered one such mutation, in the gene encoding the trans-Golgi copper transporter Atp7a. Mutations in the human ATP7a gene cause Menkes disease. We have thus discovered a function for alpha-synuclein in the mammalian ER-Golgi intracellular transport pathway, and are now studying how alpha-synuclein buffers the effects of the Atp7a mutation.Litter of mice carrying the sensitized mutation in the X-linked Atp7a gene. Mutant males are white, mutant females show a mottled coat color phenotype, and wild type littermates are agouti in color. In the absence of alpha-synuclein, Atp7a mutant females have a significantly increased rate of early death.