title: Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.
abstract: BACKGROUND
  The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration.
  
  
  RESULTS
  Nitrotyrosine (NT)-modified alpha-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss.
  
  
  CONCLUSIONS
  These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.
authors.affiliation: Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Benner
authors.forename: Rebecca
authors.initials: R
authors.lastname: Banerjee
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Reynolds
authors.forename: Simon
authors.initials: S
authors.lastname: Sherman
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Pisarev
authors.forename: Vladislav
authors.initials: V
authors.lastname: Tsiperson
authors.forename: Craig
authors.initials: C
authors.lastname: Nemachek
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology*; D009566:Nitrates / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D051844:alpha-Synuclein / Q000276:immunology* / Q000378:metabolism
chemical_list: D000939:Epitopes; D009566:Nitrates; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine