Microglial activation mediates neurodegeneration related to oligodendroglial α-synucleinopathy: Implications for multiple system atrophy

Authors

  • Nadia Stefanova MD, PhD,

    1. Clinical Neurobiology Unit, Neurodegeneration Research Laboratory, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
    Search for more papers by this author
  • Markus Reindl PhD,

    1. Clinical Neurobiology Unit, Neurodegeneration Research Laboratory, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
    Search for more papers by this author
  • Manuela Neumann MD,

    1. Center for Neuropathology and Prion Research Brain Bank, University of Munich, Germany
    Search for more papers by this author
  • Philipp J. Kahle PhD,

    1. Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, Germany
    Search for more papers by this author
  • Werner Poewe MD,

    1. Clinical Neurobiology Unit, Neurodegeneration Research Laboratory, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
    Search for more papers by this author
  • Gregor K. Wenning MD, PhD

    Corresponding author
    1. Clinical Neurobiology Unit, Neurodegeneration Research Laboratory, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
    • Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author

Abstract

The role of microglial activation in multiple system atrophy (MSA) was investigated in a transgenic mouse model featuring oligodendroglial α-synuclein inclusions and loss of midbrain dopaminergic neurons by means of histopathology and morphometric analysis. Our findings demonstrate early progressive microglial activation in substantia nigra pars compacta (SNc) associated with increased expression of iNOS and correlating with dopaminergic neuronal loss. Suppression of microglial activation by early long-term minocycline treatment protected dopaminergic SNc neurons. The results suggest that oligodendroglial overexpression of α-synuclein may induce neuroinflammation related to nitrosive stress which is likely to contribute to neurodegeneration in MSA. Further, we detected increased toll-like receptor 4 immunoreactivity in both transgenic mice and MSA brains indicating a possible signaling pathway in MSA which needs to be further studied as a candidate target for neuroprotective interventions. © 2007 Movement Disorder Society

Ancillary