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

Genetic modifier screens provide a useful tool, in diverse organisms from to and mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine α-synuclein (). Human was the first gene linked to familial Parkinson's disease. Since the discovery of the genetic link of to Parkinson's nearly three decades ago, numerous studies have investigated the normal function of SNCA protein with divergent roles associated with different cellular compartments. Understanding of the normal function of murine Snca is complicated by the fact that mice with homozygous null mutations live a normal lifespan and have only subtle synaptic deficits. Here, we report that the first genetic modifier (a sensitized mutation) that was identified in our screen was the X-linked gene, . In humans, mutations in are linked to to Menkes disease, a disease with pleiotropic phenotypes that include a severe neurological component. encodes a trans-Golgi copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network. Male mice that carry a mutation in die within 3 weeks of age regardless of genotype. In contrast, here we show that disruption modifies the phenotype of in female mice. 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 ATPase copper transporting alpha. Thus, null mutations sensitize female mice to mutations in , suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. Although data has suggested diverse functions for human and mouse α-synuclein proteins in multiple cell compartments, this is the first demonstration via use of genetic screening to demonstrate that Snca protein may function in the ER-Golgi system in the mammalian brain in a sex-dependent manner.