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

## TL;DR

This study uses fruit flies to model human lysosomal storage disorders, showing similar disease features and offering a platform for developing new treatments.

## Contribution

The study introduces a Drosophila model system for LSDs with age- and sex-dependent phenotypes, enabling molecular and therapeutic research.

## Key findings

- Transgenic flies showed shortened lifespans and progressive locomotor decline, mirroring human LSD pathologies.
- Phenotypes were observed to follow age- and sex-dependent patterns, supporting the functional relevance of selected gene orthologs.
- The model provides a platform for high-throughput genetic and pharmacological screening for LSD therapies.

## Abstract

Lysosomal storage disorders (LSDs) are a group of rare inherited diseases caused by mutations in the genes encoding the proteins involved in normal lysosomal functions, leading to an accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. The 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 the Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain–midgut axis via the use of GAL4/UAS and RNAi combined technologies. Transgenic fly models presented key features of human LSD pathologies, including significantly shortened lifespans and a progressive locomotor decline that serves as a 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, moving towards development of new therapeutically beneficial drug-based regimens and mutant gene-rescue schemes.