The
hereditary spastic paraplegias (SPG1-33) comprise a cluster of inherited
neurological disorders characterized principally by lower extremity spasticity and weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Mutations in the gene encoding the large oligomeric
GTPase atlastin-1 are responsible for
SPG3A, a common
autosomal dominant hereditary spastic paraplegia. Here we describe a family of human
GTPases, atlastin-2 and -3 that are closely related to atlastin-1. Interestingly, while atlastin-1 is predominantly localized to vesicular tubular complexes and cis-Golgi cisternae, mostly in brain, atlastin-2 and -3 are localized to the endoplasmic reticulum (ER) and are most enriched in other tissues. Knockdown of atlastin-2 and -3 levels in HeLa cells using
siRNA (
small interfering RNA) causes disruption of Golgi morphology, and these Golgi structures remain sensitive to
brefeldin A treatment. Interestingly, expression of
SPG3A mutant or dominant-negative atlastin
proteins lacking
GTPase activity causes prominent inhibition of ER reticularization, suggesting a role for atlastin
GTPases in the formation of three-way junctions in the ER. However, secretory pathway trafficking as assessed using
vesicular stomatitis virus G protein fused to
green fluorescent protein (VSVG-GFP) as a reporter was essentially normal in both knockdown and dominant-negative overexpression conditions for all atlastins. Thus, the atlastin family of
GTPases functions prominently in both ER and Golgi morphogenesis, but they do not appear to be required generally for anterograde ER-to-Golgi trafficking. Abnormal morphogenesis of the ER and Golgi resulting from mutations in atlastin-1 may ultimately underlie
SPG3A by interfering with proper membrane distribution or polarity of the long corticospinal motor neurons.