The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling

Hum Mol Genet. 2009 Oct 15;18(20):3805-21. doi: 10.1093/hmg/ddp324. Epub 2009 Jul 20.

Abstract

The hereditary spastic paraplegias (HSPs) are genetic conditions characterized 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 localize to endosomes. One of these is NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) and we have shown recently that its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP) signalling, 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 signalling. 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 signalling involves downregulation 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 signalling. Since BMP signalling is important for distal axonal function, we propose that dysregulation of BMP signalling 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Cycle / genetics
  • Cell Cycle Proteins
  • Cell Line
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Endosomes / genetics
  • Endosomes / metabolism
  • Humans
  • Neurons / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Proteins / genetics
  • Proteins / metabolism*
  • Signal Transduction*
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism*
  • Spastin

Substances

  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Proteins
  • SPART protein, human
  • ZC3HC1 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • Adenosine Triphosphatases
  • Spastin
  • SPAST protein, human