Functional Conservation of the Pathological Effects of Human Mutations In. KIF5A in a Drosophila Model of Autosomal-Dominant

Impairments in intracellular transport are the hallmark of many neurological diseases including hereditary spastic paraplegia (HSP). HSP is a genetically heterogeneous neurodegenerative disorder causing spastic weakness of the lower extremities. On the cellular level the disease is characterized by distal axonopathy that affects the longest axons in the corticospinal tract. At present at least 45 HSP loci have been described. Mutations in atlastin and spastin (accounting for around 50% of all HSP cases) as well as mutations in 6 other identified SPG genes: (kif5a, nipa, spatacsin, spastizin, spartin and maspardin) have been implicated in disturbance of axonal transport and membrane trafficking. The fact that spinal neurons with the longest axons are selectively affected might be due to their morphology. They have substantial dependence on efficient axonal transport of organelles, molecules and signals to and from nerve terminals. Disturbances in antero- grade and retrograde transport might interfere with efficient synaptic function/maintenance and maintenance of the axon itself. Perturbations of axonal transport emerge as a common patho- logical mechanism in many HSP cases. To test this hypothesis and to further probe the pathological mechanisms we generated a Drosophila model for SPG10, an autosomal dominant form of HSP. SPG10 is caused by mutations in KIF5A gene, which codes for the heavy chain of the neuronal microtubule motor Kinesin-1. The Kinesin-1 family represents the major anterograde motor complex