Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.

Zhao J, Hedera P
Mol Cell Neurosci. 2013 52: 87-96

PMID: 23079343 · PMCID: PMC3587122 · DOI:10.1016/j.mcn.2012.10.005

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (21)

Animals Blotting, Western Bone Morphogenetic Protein Receptors, Type II Cells, Cultured Chlorocebus aethiops COS Cells Flow Cytometry GTP-Binding Proteins HEK293 Cells Humans Immunohistochemistry Immunoprecipitation Membrane Proteins Microscopy, Confocal Mutagenesis, Site-Directed Mutation Neurons Protein Transport Rats Spastic Paraplegia, Hereditary Transfection

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