SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.
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.
Zhu
Peng-Peng
PP
Cellular Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, 35 Convent Drive, Bethesda, MD 20892, USA.
Soderblom
Cynthia
C
Tao-Cheng
Jung-Hwa
JH
Stadler
Julia
J
Blackstone
Craig
C
D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins; D020439:Growth Cones / Q000378:metabolism*; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C513123:Atl1 protein, rat; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins