SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia

  • Neuron. 2014 Jun 4;82(5):1074-87. doi: 10.1016/j.neuron.2014.04.022.
Simon Glerup  1 ,  Ditte Olsen  2 ,  Christian B Vaegter  2 ,  Camilla Gustafsen  2 ,  Susanne S Sjoegaard  2 ,  Guido Hermey  3 ,  Mads Kjolby  2 ,  Simon Molgaard  4 ,  Maj Ulrichsen  2 ,  Simon Boggild  2 ,  Sune Skeldal  5 ,  Anja N Fjorback  2 ,  Jens R Nyengaard  6 ,  Jan Jacobsen  7 ,  Dirk Bender  7 ,  Carsten R Bjarkam  8 ,  Esben S Sørensen  9 ,  Ernst-Martin Füchtbauer  9 ,  Gregor Eichele  10 ,  Peder Madsen  5 ,  Thomas E Willnow  11 ,  Claus M Petersen  5 ,  Anders Nykjaer  12
Affiliations
  • 1. The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: [email protected].
  • 2. The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
  • 3. The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
  • 4. The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; MIND Center, Stereology and Electron Microscopy Laboratory, Aarhus University, 8000 C Aarhus, Denmark.
  • 5. The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark.
  • 6. MIND Center, Stereology and Electron Microscopy Laboratory, Aarhus University, 8000 C Aarhus, Denmark.
  • 7. PET Center, Aarhus University Hospital, 8000 C Aarhus, Denmark.
  • 8. Department of Neurosurgery, Aarhus University Hospital, 8000 C Aarhus, Denmark.
  • 9. Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
  • 10. Department of Genes and Behaviour, Max Plack Institute, 37077 Göttingen, Germany.
  • 11. Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
  • 12. The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, 8000 C Aarhus, Denmark; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: [email protected].
PMID: 24908487 DOI: 10.1016/j.neuron.2014.04.022
Abstract

Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell Apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with Apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.