Journal Article

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

Peng-Peng Zhu, Cynthia Soderblom, Jung-Hwa Tao-Cheng, Julia Stadler and Craig Blackstone

in Human Molecular Genetics

Volume 15, issue 8, pages 1343-1353
Published in print April 2006 | ISSN: 0964-6906
Published online March 2006 | e-ISSN: 1460-2083 | DOI:
SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development

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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.

Journal Article.  6404 words.  Illustrated.

Subjects: Genetics and Genomics

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