Human Molecular Genetics Advance Access published online on March 14, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl054
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1 Cellular Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
* To whom correspondence should be addressed. The hereditary spastic paraplegias (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 hereditary spastic paraplegia. A distinguishing feature of SPG3A is its frequent very 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 microscopy 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 due to loss of atlastin-1 function.
Received January 12, 2006
Revised March 7, 2006
Accepted March 7, 2006
Article
SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development
Peng-Peng Zhu 1,
Cynthia Soderblom 1,
Jung-Hwa Tao-Cheng 2,
Julia Stadler 1,
and
Craig Blackstone 3 *
2 Electron Microscopy Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
3 Cellular Neurology Unit, NINDS, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, Room 2C-913, 35 Convent Drive, Bethesda, Maryland 20892-3704
Craig Blackstone, E-mail: blackstc{at}ninds.nih.gov
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