A new model for spastic paraplegia
HSPs are characterised by degeneration of longer spinal cord motor tract axons (axonopathy) in the brain and spinal cord. As the motor neurons degenerate, messages cannot be transmitted correctly to muscles and spasticity and weakness ensue. Most of the genes implicated in the development of HSPs encode intracellular membrane proteins, principally endoplasmic reticulum (ER). Reticulons (RTNs) are a group of membrane proteins located on the cell ER and regulate ER function and structure. As the reticulon has also been implicated in axonopathy, the 'Spastic paraplegia genes and endosomal signaling in Drosophila' (Paraplegia Endosomes) project characterised the effects of loss of reticulon in Drosophila. Researchers found that the Rtnl1 gene, the Drosophila orthologue of four human reticulon genes, is required for tubular ER formation. Rtnl1 is widely expressed in nervous tissue and is required for ER maintenance and the microtubule cytoskeleton in long axons. Furthermore, loss of Rtnl1 caused fewer mitochondria in the posterior nerve terminal boutons in the muscle. Significantly, adult flies presented movement deficits similar to those described in spastin and atlastin mutants. Spastin and atlastin are two proteins mutated in HSP patients but there was no evidence that these behavioural phenotypes were relevant to lower limb spasticity symptoms in humans. To explain this, project scientists suggested that ER-shaping proteins are necessary for motor axon maintenance in Drosophila. Data from the research of Paraplegia Endosomes supports the use of Rtnl1 knockdown mutants as a novel model for the study of tubular ER defects in vivo. Further study will add to the knowledge platform on HSPs already established by the project.
