Objective: To identify genetic modifiers of decreased locomotion and neuromuscular junction defects associated with atlastin knockdown in motor neurons.

Background: Hereditary 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.

Method: We screened for genomic regions that modify the climbing performance or viability of flies expressing atl RNAi in motor neurons. We tested 364 deficiencies spanning chromosomes two and three. We perform functional analyses of candidate genes by driving RNAis in motor neurons using the UAS-GAL4 system. We carry out genetic interaction experiments using atl² and Su(z)2^1.a1 alleles and atl–RNAi.

Results: We found 35 enhancer and four suppressor regions of the climbing phenotype. We found that candidate genomic regions can also rescue atlastin 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 that atl interacts genetically with Su(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 by atl alleles.

Conclusion: Our results identify new candidate genes and epigenetic regulation as a mechanism modifying neuronal atl pathogenic phenotypes, providing new targets for pharmacological research.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-atlastin-genetic-modifiers-in-a-hereditary-spastic-paraplegia-model-in-drosophila/