Identification of atlastin genetic modifiers in a model of hereditary spastic paraplegia in Drosophila

AbstractHereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by progressive dysfunction of corticospinal motor neurons. Mutations in Atlastin1/Spg3, a small GTPase required for membrane fusion in the endoplasmic reticulum, are responsible for 10% of HSPs. Patients with the same Atlastin1/Spg3 mutation present high variability in age at onset and severity, suggesting a fundamental role of the environment and genetic background. Here, we used aDrosophila model of HSPs to identify genetic modifiers of decreased locomotion associated withatlastin knockdown in motor neurons. First, we screened for genomic regions that modify the climbing performance or viability of flies expressingatl RNAi in motor neurons. We tested 364 deficiencies spanning chromosomes two and three and found 35 enhancer and four suppressor regions of the climbing phenotype. We found that candidate genomic regions can also rescueatlastin effects at synapse morphology, suggesting a role in developing or maintaining the neuromuscular junction. Motor neuron-specific knockdown of 84 genes spanning candidate regions of the second chromosome identified 48 genes required for climbing behavior in motor neurons and 7 for viability, mapping to 11 modifier regions. We found thatatl interacts genetically withSu(z)2, a component of the Polycomb repressive complex 1, suggesting that epigenetic regulation plays a role in the variability of HSP-like phenotypes caused byatl alleles. Our ...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research