Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.
Disruption of the bone morphogenic protein (BMP)-linked signaling pathway has been suggested as an important factor in the development of hereditary spastic paraplegia (HSP). HSP-causing proteins spastin, spartin and NIPA1 were reported to inhibit the BMP pathway. We have previously shown a strong interaction of NIPA1 and atlastin-1 proteins. Hence, we investigated the role of another HSP-associated protein atlastin-1 in this signaling cascade. Endogenous and expressed atlastin-1 showed a strong interaction with BMP receptors II (BMPRII) and analyzed missense, HSP-causing mutations R239C and R495W disrupted BMPRII trafficking to the cell surface. BMPRII does not require the presence of atlastin-1 because knockdown expression of atlastin-1 did not alter endogenous BMPRII cellular distribution. Expression of mutant forms of atlastin-1 also interfered with the signaling response to BMP4 stimulation and reduced phosphorylation of Smad 1/5 proteins. Our results suggest that HSP-causing atlastin-1 mutations exhibit a dominant-negative effect on trafficking of BMPRII, which disrupts the BMP pathway in neurons. This, together with previously demonstrated inhibition of atlastin-1 of BMP pathway, further supports the role of this signaling cascade in axonal maintenance and axonal degeneration, which is seen in various types of HSP.
Department of Neurology, Vanderbilt University, Nashville, TN, USA.
Jiali
J
Zhao
Peter
P
Hedera
D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D051381:Rats; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D008565:Membrane Proteins; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; C440006:ATL1 protein, human; D019204:GTP-Binding Proteins