CG13531 nakavt mutantlarının meyve sineğinde SPG11-ilişkili motor nöron nöropati modeli olarak karakterizasyonu

Motor neuron diseases (MNDs) are a large group of degenerative disorders with multiple genes involved in pathogenesis. These diseases often have complex contributing factors, which can influence the effectiveness of treatment. Patients diagnosed with the same MND but carrying different mutations may respond differently to the same treatment. While high-frequency causative gene mutations in populations are studied with well-defined models to uncover disease progression and treatment, less-frequent gene mutations and their associated mechanisms remain poorly understood. The Spastic Paraplegia Gene 11 (SPG11) is one such gene associated with motor neuron diseases that currently lacks a Drosophila melanogaster model. SPG11 encodes for the spatacsin protein, which plays a role in various cellular processes. The loss of SPG11 function causes motor neuron degeneration, movement difficulties, and thin corpus callosum in patients. The Drosophila melanogaster CG13531 gene is the only ortholog candidate of SPG11, but a fruit fly model for this gene has not yet been established. This study aimed to establish a well-defined Drosophila model for SPG11-related diseases that could be used in drug repurposing and screening studies. A knockout model of CG13531 was generated using the CRIMIC method and thoroughly examined. Results demonstrated that the knockout mutant had reduced locomotor ability and survival rates. Additionally, motor neuron morphology was altered, confirming the observed locomotor deficits. An assessment of midline-crossing neurons was performed to understand whether the knockout model reflects the thin corpus callosum phenotype observed in patients. Overall, these findings suggest that the CG13531 knockout model can effectively reflect SPG11-related diseases, providing a valuable tool for understanding the disease mechanisms and testing therapeutic approaches.