Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model

PLoS Genet. 2012;8(11):e1003066. doi: 10.1371/journal.pgen.1003066. Epub 2012 Nov 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axonal Transport / genetics
  • Axonal Transport / physiology
  • Disease Models, Animal
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics*
  • Gene Expression
  • Humans
  • Kinesin / genetics*
  • Mice
  • Microtubules / genetics
  • Microtubules / metabolism
  • Mutation
  • Spastic Paraplegia, Hereditary / genetics*
  • Synapses / genetics
  • Synapses / pathology


  • Drosophila Proteins
  • Kif5A protein, mouse
  • Khc protein, Drosophila
  • Kinesin

Supplementary concepts

  • Spastic paraplegia 10, autosomal dominant

Grant support

This work was supported by a grant from the Hertie Foundation to RS and TMR, by a grant from the Fritz Thyssen Foundation (grant to TMR, and by a grant from the Center for Clinical Research (IKFZ) Tübingen (grant 170-0-0) to RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.