title: The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity.
abstract: BACKGROUND
  Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein α-synuclein (α-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by α-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA).
  
  
  OBJECTIVE
  The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach.
  
  
  METHODS
  We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models [including DJ-1 knockout (-/-) mice] to investigate DJ-1 in dopaminergic degeneration.
  
  
  RESULTS
  We found that in PC12/TetOn cells overexpressing α-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased α-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of α-syn (TAT-α-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-α-syn (A30P) in the striatum of DJ-1 (-/-) animals, dopamine was depleted more than in the control strain.
  
  
  CONCLUSIONS
  DJ-1 appears to have a protective role against dopaminergic degeneration triggered by α-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD.
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Batelli
authors.forename: Roberto William
authors.initials: RW
authors.lastname: Invernizzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Negro
authors.forename: Eleonora
authors.initials: E
authors.lastname: Calcagno
authors.forename: Serena
authors.initials: S
authors.lastname: Rodilossi
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Diego
authors.initials: D
authors.lastname: Albani
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016627:Oxidopamine / Q000378:metabolism / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000071617:Protein Deglycase DJ-1; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015513:Oncogene Proteins; D051844:alpha-Synuclein; D016627:Oxidopamine; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1