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Mutations in  spastin  are the most frequent cause of the neurodegenerative disease autosomal dominant-hereditary spastic paraplegia (AD-HSP).  Drosophila melanogaster  lacking  spastin  exhibit striking behavioral similarities to human patients suffering from AD-HSP, suggesting conservation of Spastin function between the species. Consistent with this, we show that exogenous expression of wild-type  Drosophila  or human  spastin  rescues behavioral and cellular defects in  spastin  null flies equivalently. This enabled us to generate genetically representative models of AD-HSP, which arises from dominant mutations in  spastin  rather than a complete loss of the gene. Flies co-expressing one copy of wild-type human  spastin  and one encoding the K388R catalytic domain mutation in the fly  spastin  null background, exhibit aberrant distal synapse morphology and microtubule distribution, similar to but less severe than  spastin  nulls. R388 or a separate nonsense mutation act dominantly and are furthermore sufficient to confer partial rescue, supporting  in vitro  evidence for additional, non-catalytic Spastin functions. Using this model, we tested the observation from human pedigrees that S44L and P45Q are trans-acting modifiers of mutations affecting the Spastin catalytic domain. As in humans, both L44 and Q45 are largely silent when heterozygous, but exacerbate mutant phenotypes when expressed in trans with R388. These transgenic ‘AD-HSP’ flies therefore provide a powerful and tractable model to enhance our understanding of the cellular and behavioral consequences of human  spastin  mutations and test hypotheses directly relevant to the human disease.

Functional conservation of human Spastin in a Drosophila model of autosomal dominant-hereditary spastic paraplegia