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PMID: 18167537 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.

PloS one ·Vol. 3 ·No. 1 ·2008-01-02 ·Pages e1376

Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE

Abstract

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. 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. 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.

MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology Adoptive Transfer Animals Cells, Cultured Enzyme-Linked Immunosorbent Assay Epitopes/immunology Flow Cytometry Immunohistochemistry Male Mice Mice, Inbred C57BL Neurons/pathology Nitrates/metabolism Substantia Nigra/drug effects,pathology alpha-Synuclein/immunology,metabolism
Chemicals
Epitopes Nitrates alpha-Synuclein 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Benner Eric J
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Banerjee Rebecca
Reynolds Ashley D
Sherman Simon
Pisarev Vladimir M
Tsiperson Vladislav
Nemachek Craig
Ciborowski Pawel
Przedborski Serge
Mosley R Lee
Gendelman Howard E
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0001376
Published
2008-01-02
Epub
2008-00-02
Pages
e1376
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2147051
Subset
IM
Grants
NINDS NIH HHS · NS11766 · United States
NINDS NIH HHS · NS36136 · United States
NINDS NIH HHS · P01 NS043985 · United States
NIA NIH HHS · R01 AG021617 · United States
NINDS NIH HHS · P50 NS038370 · United States
NINDS NIH HHS · NS38370 · United States
NIEHS NIH HHS · ES013177 · United States
NIA NIH HHS · AG021617 · United States
NINDS NIH HHS · R21 NS049264 · United States
NIMH NIH HHS · MH64570 · United States
NINDS NIH HHS · NS049264 · United States
NINDS NIH HHS · NS43985 · United States
NIEHS NIH HHS · R21 ES013177 · United States
NIMH NIH HHS · P01 MH064570 · United States
NINDS NIH HHS · NS007488 · United States
NINDS NIH HHS · P01 NS011766 · United States
NINDS NIH HHS · T32 NS007488 · United States
NINDS NIH HHS · R01 NS042269 · United States
NINDS NIH HHS · NS42269 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0001376 PMC Full Text View journal details
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