title: Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model.
abstract: Hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative disorders characterized by spastic weakness of the lower extremities. We have generated a Drosophila model for HSP type 10 (SPG10), caused by mutations in KIF5A. KIF5A encodes the heavy chain of kinesin-1, a neuronal microtubule motor. Our results imply that SPG10 is not caused by haploinsufficiency but by the loss of endogenous kinesin-1 function due to a selective dominant-negative action of mutant KIF5A on kinesin-1 complexes. We have not found any evidence for an additional, more generalized toxicity of mutant Kinesin heavy chain (Khc) or the affected kinesin-1 complexes. Ectopic expression of Drosophila Khc carrying a human SPG10-associated mutation (N256S) is sufficient to disturb axonal transport and to induce motoneuron disease in Drosophila. Neurofilaments, which have been recently implicated in SPG10 disease manifestation, are absent in arthropods. Impairments in the transport of kinesin-1 cargos different from neurofilaments are thus sufficient to cause HSP-like pathological changes such as axonal swellings, altered structure and function of synapses, behavioral deficits, and increased mortality.
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Füger
authors.forename: Vrinda
authors.initials: V
authors.lastname: Sreekumar
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Jeannine V
authors.initials: JV
authors.lastname: Kern
authors.forename: Doychin T
authors.initials: DT
authors.lastname: Stanchev
authors.forename: Carola D
authors.initials: CD
authors.lastname: Schneider
authors.forename: Kathrin N
authors.initials: KN
authors.lastname: Karle
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Daub
authors.forename: Vera K
authors.initials: VK
authors.lastname: Siegert
authors.forename: Matthias
authors.initials: M
authors.lastname: Flötenmeyer
authors.forename: Heinz
authors.initials: H
authors.lastname: Schwarz
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Rasse
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D051379:Mice; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D013569:Synapses / Q000235:genetics / Q000473:pathology
chemical_list: D029721:Drosophila Proteins; C507512:Kif5A protein, mouse; C515209:Khc protein, Drosophila; D016547:Kinesins