Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice.

Human , which encodes a-synuclein protein (), was the first gene linked to familial Parkinson's disease (PD). Since the discovery of the genetic link of to Parkinson's nearly three decades ago, many studies have investigated the normal function of protein. However, understanding of the normal function of is complicated by the lack of a reliable mammalian model of PD; indeed, mice with homozygous null mutations in the gene live a normal lifespan and have only subtle synaptic deficits. Here, we report the first genetic modifier (a sensitized mutation) of a murine null mutation, namely the an X-linked gene that escapes inactivation in both mice and humans. In humans, mutations in are linked to Menkes disease, a disease with pleiotropic and severe neurological phenotypes. encodes a copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network; under some conditions, protein may also act to increase copper flux across the cell membrane. Male mice that carry a mutation in die within 3 weeks of age regardless of genotype. In contrast, female mice that carry the mutation, on an null background, die earlier (prior to 35 days) at a significantly higher rate than those that carry the mutation on a wildtype background. Thus, null mutations sensitize female mice to mutations in suggesting that protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. This study adds to the growing literature suggesting that alterations in a-synuclein structure and/or quantity may manifest in neurological differences in males and females including phenotypes of developmental delays, seizures, muscle weakness and cognitive function.