Other genes and epigenetic regulation play a part
This study helps explain high variability in the SPG3A phenotype, specifically age at onset and disease severity. Fruit flies were used to identify genetic modifiers of decreased movement that occurs with SPG3A. The SPG3A protein Atlastin was found to interact with multiple other genes that influence the level of expression of this protein. Environmental factors (epigenetic regulation) were also found to modify protein expression, thus leading to variability in the resulting phenotype.
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.
Here, we used a Drosophila model of HSPs to identify genetic modifiers of decreased locomotion associated with atlastin knockdown in motor neurons. First, 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 and 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. Our results identify new candidate genes and epigenetic regulation as a mechanism modifying neuronal atl pathogenic phenotypes, providing new targets for clinical studies.
SOURCE: Hum Genet. 2023 Jun 27.
doi: 10.1007/s00439-023-02577-7. Online ahead of print. PMID: 37368047 © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Identification of atlastin genetic modifiers in a model of hereditary spastic paraplegia in Drosophila
1. Programa de Genética Humana, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, 8380453, Santiago, Chile.
2. Departamento de Neurociencia, Biomedical Neuroscience Institute (BNI), Facultad de Medicina, Universidad de Chile, Independencia 1027, 8380453, Santiago, Chile.
3. Escuela de Kinesiología, Facultad de Medicina y Ciencias de la Salud, Center for Integrative Biology (CIB), Universidad Mayor, Santiago, Chile.
4. Programa de Genética Humana, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, 8380453, Santiago, Chile.
5. Departamento de Neurociencia, Biomedical Neuroscience Institute (BNI), Facultad de Medicina, Universidad de Chile, Independencia 1027, 8380453, Santiago, Chile.