Human Molecular Genetics Advance Access originally published online on March 14, 2006
Human Molecular Genetics 2006 15(8):1343-1353; doi:10.1093/hmg/ddl054
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Published by Oxford University Press 2006
SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development
1Cellular Neurology Unit and 2Electron Microscopy Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
* To whom correspondence should be addressed at: Cellular Neurology Unit, NINDS, National Institutes of Health, Building 35, Room 2C-913, 35 Convent Drive, Bethesda, MD 20892-3704, USA. Tel: +1 3014519680; Fax: +1 3014804888; Email: blackstc{at}ninds.nih.gov
Received January 12, 2006; Accepted March 7, 2006
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.
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