2. Academic Validation
  3. SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia

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

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.

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