SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development

Hum Mol Genet. 2006 Apr 15;15(8):1343-53. doi: 10.1093/hmg/ddl054. Epub 2006 Mar 14.

Abstract

The hereditary spastic paraplegias (HSPs) (SPG1-29) comprise a group of inherited neurological disorders characterized principally by spastic lower extremity weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Mutations in the gene encoding the dynamin superfamily member atlastin-1, an oligomeric GTPase highly localized to the Golgi apparatus in the adult brain, are responsible for SPG3A, a common autosomal dominant HSP. A distinguishing feature of SPG3A is its frequent early onset, raising the possibility that developmental abnormalities may be involved in its pathogenesis. Here, we demonstrate that several missense SPG3A mutant atlastin-1 proteins have impaired GTPase activity and thus may act in a dominant-negative, loss-of-function manner by forming mixed oligomers with wild-type atlastin-1. Using confocal and electron microscopies, we have also found that atlastin-1 is highly enriched in vesicular structures within axonal growth cones and varicosities as well as at axonal branch points in cultured cerebral cortical neurons, prefiguring a functional role for atlastin-1 in axonal development. Indeed, knock-down of atlastin-1 expression in these neurons using small hairpin RNAs reduces the number of neuronal processes and impairs axon formation and elongation during development. Thus, the "long axonopathy" in early-onset SPG3A may result from abnormal development of axons because of loss of atlastin-1 function.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Axons / ultrastructure*
  • Brain / cytology
  • Brain / metabolism
  • Central Nervous System / growth & development
  • Central Nervous System / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • GTP-Binding Proteins
  • Growth Cones / metabolism*
  • Immunohistochemistry
  • Microscopy, Electron
  • Neurons / cytology
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism

Substances

  • DNA-Binding Proteins
  • Atl1 protein, rat
  • GTP Phosphohydrolases
  • GTP-Binding Proteins