Datensatz

Zusammenfassung

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.