Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs, owing to progressive retrograde degeneration of the long corticospinal axons. Mutations in the gene spastin (SPG4) are responsible for the prevailing form of pure HSP. Spastin is an ATPase that contains a microtubule-interacting domain and has been implicated in several processes involving remodeling of membrane structures. Moreover, spastin harbors a lipid droplet (LD) targeting sequence that allows its targeting to LDs surface. Our group has previously shown that the highly conserved Drosophila spastin homolog (Dspastin) regulates microtubule stability and synaptic function of the Drosophila larval neuromuscular junction.
Considering the lipid droplets formation and maintenance as a possible common pathway in HSP neurodegeneration, we wanted to further investigate a possible role of spastin in lipid metabolism.
We observed that ubiquitous overexpression of Dspastin in Drosophila increased triacylglycerol levels and led to bigger and less numerous LDs in fat bodies. In contrast, Dspastin specific overexpression in skeletal muscles or nerves increased LDs number. Downregulation of Dspastin and expression of a dominant-negative variant (Dspastin K467R) decreased LDs number in Drosophila nerves, skeletal muscles and fat bodies, and reduced triacylglycerol levels in the whole larva.
Our results suggest the role of spastin as a regulator of lipid metabolism, enforces and strongly support the recent discoveries that dysfunction of LDs in axons may contribute to the pathogenesis of HSP.