Genetic Modeling of Lysosomal Storage Disorders (LSDs), in the Brain-Midgut Axis of Drosophila melanogaster, During Aging

Lysosomal Storage Disorders (LSDs) are a group of rare inherited diseases caused by mutations in genes encoding proteins involved in normal lysosomal functions, leading to accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. Development of powerful and reliable animal-model systems that can in vivo recapitulate human LSD pathologies is critical for understanding disease mechanisms and advancing therapeutic strategies. In this study, we identified Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain-midgut axis via engagement of GAL4/UAS and RNAi combined technologies. Transgenic fly models were presented with key features of human LSD pathologies, including significantly shortened lifespan and progressive locomotor decline that serves as measure for neuromuscular disintegration, following age- and sex-dependent patterns. These phenotypic parallels in pathology strongly support the functional relevance of the selected orthologs and underscore the value of Drosophila as a versatile, in vivo, model system for advanced LSD-pathology research, offering state-of-the-art genetic tools for molecularly dissecting disease mechanisms, and providing cutting-edge novel platforms for high-throughput genetic and/or pharmacological screening, towards development of therapeutically beneficial, new, drug-based regimens and mutant gene-rescue schemes.