Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia

Mutations in ATL1 are a frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), yet patients display a wide range of clinical severity, from slowly progressive "pure" to severe, early-onset "complex" forms. The cellular mechanisms underlying this heterogeneity remain poorly defined, and mammalian model systems have thus far failed to distinguish between these subtypes. This study investigates the cellular basis of these clinically distinct forms of HSP using Drosophila models carrying homologous disease-causing mutations in the gene encoding Atlastin-1 (ATL1). Drosophila harbouring a complex ATL1-HSP mutation display reduced locomotor function, impaired development, and decreased survival relative to those carrying mutations associated with pure ATL1-HSP, recapitulating key aspects of clinical heterogeneity. Moreover, cellular analyses identify distinct pathological features across genotypes. Models of pure ATL1-HSP display disrupted lipid homeostasis, including lipid droplet accumulation within nerves comprising long motor neuron axons, which is partially ameliorated by treatment with a liver X receptor (LXR) agonist. In contrast, complex ATL1-HSP Drosophila lack lipid droplet abnormalities and do not respond to LXR activation but instead show disruption of the neuronal endoplasmic reticulum, consistent with aberrant ER network regulation. Together, these findings suggest that different mutations in Atl give rise to distinct cellular perturbations, suggesting a potential basis for phenotypic heterogeneity in ATL1-HSP.