Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy

Am J Pathol. 2005 Mar;166(3):869-76. doi: 10.1016/s0002-9440(10)62307-3.

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism unresponsive to dopaminergic therapy, cerebellar ataxia, and dysautonomia. Neuropathology shows a characteristic neuronal multisystem degeneration that is associated with widespread oligodendroglial alpha-synuclein (alpha-SYN) inclusions. Presently no animal model completely replicates the specific neuropathology of MSA. Here we investigated the behavioral and pathological features resulting from oligodendroglial alpha-SYN overexpression in transgenic mice exposed to mitochondrial inhibition by 3-nitropropionic acid. In transgenic mice 3-nitropropionic acid induced or augmented motor deficits that were associated with MSA-like pathology including striatonigral degeneration and olivopontocerebellar atrophy. Widespread astrogliosis and microglial activation were also observed in the presence of alpha-SYN in oligodendrocytes. Our results indicate that combined mitochondrial inhibition and overexpression of oligodendroglial alpha-SYN generates a novel model of MSA that may be useful for evaluating both pathogenesis and treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, Myelomonocytic / biosynthesis
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Disease Models, Animal
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism
  • Movement
  • Movement Disorders / genetics
  • Multiple System Atrophy / genetics
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics*
  • Neurons / metabolism
  • Nitro Compounds
  • Oligodendroglia / metabolism*
  • Oxidative Stress*
  • Propionates / pharmacology
  • Synucleins
  • Time Factors
  • alpha-Synuclein

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Nerve Tissue Proteins
  • Nitro Compounds
  • Propionates
  • Snca protein, mouse
  • Synucleins
  • alpha-Synuclein
  • 3-nitropropionic acid