Nerve signalling disrupted. NIPA1, spastin and spartin have all been found to be inhibitors of a protein (BMP) required for effective signaling along nerves.
The hereditary spastic paraplegias (HSPs) are genetic conditions characterised by distal axonopathy of the longest corticospinal tract axons, and so their study provides an important opportunity to understand mechanisms involved in axonal maintenance and degeneration. A group of HSP genes encode proteins that localise to endosomes. One of these is NIPA1 (non-imprinted in Angelman syndrome 1) and we have shown recently that its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP) signaling, although the relevance of this finding to the mammalian protein was not known. We show here that mammalian NIPA1 is also an inhibitor of BMP signaling. NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII. We show that the mechanism by which NIPA1 inhibits BMP signaling involves down-regulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1. In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signaling. Since BMP signaling is important for distal axonal function, we propose that dysregulation of BMP signaling could be a unifying pathological component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.
Hum Mol Genet. 2009 Jul 20.
The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signaling.
Tsang HT, Edwards TL, Wang X, Connell JW, Davies RJ, Durrington HJ, O’Kane CJ, Luzio JP, Reid E.
Cambridge Institute for Medical Research.