title: Region-Specific Alterations of Matrix Metalloproteinase Activity in Multiple System Atrophy.
abstract: BACKGROUND
  MSA is a sporadic progressive neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. The pathological hallmark of MSA is the accumulation of alpha-synuclein aggregates in the cytoplasm of oligodendrocytes along with neuronal loss and neuroinflammation, as well as blood-brain barrier dysfunction and myelin deterioration. Matrix metalloproteinases are zinc-dependent endopeptidases involved in the remodeling of the extracellular matrix, demyelination, and blood-brain barrier permeability. Several lines of evidence indicate a role for these enzymes in various pathological processes, including stroke, multiple sclerosis, Parkinson's, and Alzheimer's disease.
  
  
  METHODS
  This study aimed to assess potential alterations of matrix metalloproteinase-1, -2, -3, and -9 expression or activity in MSA postmortem brain tissue.
  
  
  RESULTS
  Gelatin zymography revealed increased matrix metalloproteinase-2 activity in the putamen, but not in the frontal cortex, of MSA patients relative to controls. Immunohistochemistry revealed increased number of glial cells positive for matrix metalloproteinase-1, -2, and -3 in the putamen and frontal cortex of MSA patients. Double immunofluorescence revealed that matrix metalloproteinase-2 and -3 were expressed in astrocytes and microglia. Only matrix metalloproteinase-2 colocalized with alpha-synuclein in oligodendroglial cytoplasmic inclusions.
  
  
  CONCLUSIONS
  These results demonstrate widespread alterations of matrix metalloproteinase expression in MSA and a pattern of increased matrix metalloproteinase-2 expression and activity affecting preferentially a brain region severely affected (putamen) over a relatively spared region (frontal cortex). Elevated matrix metalloproteinase expression may thus contribute to the disease process in MSA by promoting blood-brain barrier dysfunction and/or myelin degradation.
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Fares
authors.initials: F
authors.lastname: Bassil
authors.affiliation: Université de Poitiers, Signalisation & Transports Ioniques Membranaires, ERL7368 CNRS, Poitiers, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Monvoisin
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Canron
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|Service d'Anatomie Pathologique, CHU de Bordeaux, Bordeaux, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vital
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|Service de Neurologie, CHU de Bordeaux, Bordeaux, France.|Centre de référence atrophie multisystématisée, CHU de Bordeaux, Bordeaux, France.
authors.forename: Wassilios G
authors.initials: WG
authors.lastname: Meissner
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|Service de Neurologie, CHU de Bordeaux, Bordeaux, France.|Centre de référence atrophie multisystématisée, CHU de Bordeaux, Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Tison
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D003720:Densitometry; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008840:Microfilament Proteins; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011180:Postmortem Changes; D055815:Young Adult; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D051844:alpha-Synuclein; D020782:Matrix Metalloproteinases
keywords: alpha-synuclein; matrix metalloproteinase; multiple system atrophy; neurodegeneration; parkinsonism