Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila

Nat Commun. 2012;3:1312. doi: 10.1038/ncomms2278.

Abstract

The conserved kinases PAR-1/MARK are critically involved in processes such as asymmetric cell division, cell polarity and neuronal differentiation. Their deregulation has been implicated in diseases including Alzheimer's disease and cancer. Given the importance of PAR-1/MARK in health and disease, their activities need to be tightly controlled. However, little is known about the molecular mechanisms underlying their regulation in vivo. Here we show that in Drosophila, a phosphorylation-dependent ubiquitination mechanism restrains PAR-1 activation. Active PAR-1 generated by LKB1-controlled phosphorylation is targeted for ubiquitination and degradation by SCF (Skp, Cullin, F-box containing complex) (Slimb), whose action is antagonized by the deubiquitinating enzyme fat facets. This newly identified PAR-1-modifying module critically regulates synaptic morphology and tau-mediated postsynaptic toxicity of amyloid precursor protein (APP)/Aβ-42, the causative agents of Alzheimer's disease, at the Drosophila neuromuscular junction. Our results provide new insights into the regulation of PAR-1 in various physiological processes and offer new therapeutic strategies for diseases involving PAR-1/MARK deregulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Amyloid beta-Protein Precursor / toxicity*
  • Animals
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteolysis
  • Retina / enzymology
  • Retina / growth & development
  • Retina / metabolism
  • Synapses / enzymology
  • Synapses / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • Drosophila Proteins
  • slmb protein, Drosophila
  • tau Proteins
  • Ubiquitin-Protein Ligases
  • Protein Kinases
  • PAR-1 protein, C elegans
  • LKB1 protein, Drosophila
  • Protein-Serine-Threonine Kinases