Wings of Discovery: Using Drosophila to Decode Hereditary Spastic Paraplegia and Ataxias

Abstract

Hereditary spastic paraplegia (HSP) and hereditary ataxias (HA) are clinically and genetically heterogeneous neurodegenerative disorders that primarily affect motor coordination and neural integrity. Despite distinct pathological features, such as pyramidal tract degeneration in HSP and spinocerebellar pathway involvement in HA, these conditions share overlapping genetic pathways and mechanisms. The fruit fly Drosophila melanogaster has emerged as a powerful model organism for investigating the molecular basis of rare diseases, including HSP and HA. Its genetic tractability, rapid life cycle, and high degree of gene conservation with humans make it a cost-effective and ethically viable platform for disease modelling. In this review, we provide a comprehensive overview of Drosophila-based models for HSP and HA. We highlight the use of advanced genetic tools, including RNA interference, CRISPR/Cas9, and the GAL4/UAS system, as well as behavioral and neuroanatomical assays to model disease features. Furthermore, we discuss the application of genetic “avatars” and high-throughput drug screening platforms to test therapeutic candidates. Collectively, these models have deepened our understanding of the pathophysiology of HSP and HA, offering valuable insights for the development of targeted therapies and approaches to personalized medicine.