Common factor in several forms of HSP

Bone morphogenic protein’s role in neurons


Bone morphogenic protein (BMP) has a role in healthy nerve signalling in neurons. BMP signalling pathways have been found to be disrupted in association with spastin, spartin, NIPA-1, and now atlastin mutations causing HSP.


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 if BMP pathway, further supports the role of this signaling cascade in axonal maintenance and axonal degeneration, which is seen in various types of HSP.

SOURCE:  Mol Cell Neurosci. 2012 Oct 16. pii: S1044-7431(12)00187-X. doi: 10.1016/j.mcn.2012.10.005. [Epub ahead of print]  Copyright © 2012. Published by Elsevier Inc.  PMID:  23079343

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

Zhao J, Hedera P.

Department of Neurology, Vanderbilt University, Nashville, TN, USA.

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