Dr. Sara Lewis
Drosophila melanogaster has a long history in the study of neurodegenerative movement disorders such as Amyotrophic Lateral Sclerosis and Hereditary Spastic Paraplegia. These models manifest relevant locomotor impairments and have been used to test the effect of specific mutations, identify underlying cellular pathology, discover molecular pathways, and test pharmacological treatments. The Kruer laboratory is utilizing Drosophila melanogaster as a whole-animal model of cerebral palsy with the following goals.
Verify candidate genes with potentially disease-causing patient variants via studies of locomotor disability in the fly gene ortholog. We have found locomotor phenotypes in a subset of genes from statistical genomic gene discovery efforts, identifying these genes as likely contributors to the disorder.
Explore cellular pathology of loss-of-function variants of candidate CP genes, such as reduced size and complexity of connections at the neuron-muscle synapse or disruptions to endolysosomal compartments.
Determine if stress-induced phosphorylation of eIF2α translation factor during development causes locomotor defects. Known environmental causes of cerebral palsy (i.e. hypoxia) activate this signaling and may be an important gene-environment interaction to explain the variable severity of this common movement disorder. We are using genetic and pharmacological manipulations to test the relationship between eIF2α phosphorylation and the development oflocomotor impairments.