Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons

Eric J. Benner, Rebecca Banerjee, Ashley D. Reynolds, Simon Sherman, Vladimir M. Pisarev, Vladislav Tsiperson, Craig Nemachek, Pawel S Ciborowski, Serge Przedborski, R Lee Mosley, Howard Eliot Gendelman

Research output: Contribution to journalArticle

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Abstract

Background. The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated α-synuclein (N-α-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. Methods and Findings. Nitrotyrosine (NT)-modified α-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 α-Syn. Mice immunized with the NT-modified C-terminal tall fragment of α-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-α-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. Conclusions. These data show that NT modifications within α-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 α-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.

Original languageEnglish (US)
Article numbere1376
JournalPloS one
Volume3
Issue number1
DOIs
StatePublished - Jan 2 2008

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Synucleins
Dopaminergic Neurons
Substantia Nigra
Parkinson disease
Neurons
Immunity
T-cells
T-lymphocytes
immunity
neurons
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
T-Lymphocytes
mice
Parkinson Disease
epitopes
lymph nodes
Epitopes
Lymph Nodes
Peripheral Tolerance
neuropathology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. / Benner, Eric J.; Banerjee, Rebecca; Reynolds, Ashley D.; Sherman, Simon; Pisarev, Vladimir M.; Tsiperson, Vladislav; Nemachek, Craig; Ciborowski, Pawel S; Przedborski, Serge; Mosley, R Lee; Gendelman, Howard Eliot.

In: PloS one, Vol. 3, No. 1, e1376, 02.01.2008.

Research output: Contribution to journalArticle

Benner, Eric J. ; Banerjee, Rebecca ; Reynolds, Ashley D. ; Sherman, Simon ; Pisarev, Vladimir M. ; Tsiperson, Vladislav ; Nemachek, Craig ; Ciborowski, Pawel S ; Przedborski, Serge ; Mosley, R Lee ; Gendelman, Howard Eliot. / Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. In: PloS one. 2008 ; Vol. 3, No. 1.
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abstract = "Background. The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated α-synuclein (N-α-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. Methods and Findings. Nitrotyrosine (NT)-modified α-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 α-Syn. Mice immunized with the NT-modified C-terminal tall fragment of α-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-α-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. Conclusions. These data show that NT modifications within α-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 α-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.",
author = "Benner, {Eric J.} and Rebecca Banerjee and Reynolds, {Ashley D.} and Simon Sherman and Pisarev, {Vladimir M.} and Vladislav Tsiperson and Craig Nemachek and Ciborowski, {Pawel S} and Serge Przedborski and Mosley, {R Lee} and Gendelman, {Howard Eliot}",
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AU - Benner, Eric J.

AU - Banerjee, Rebecca

AU - Reynolds, Ashley D.

AU - Sherman, Simon

AU - Pisarev, Vladimir M.

AU - Tsiperson, Vladislav

AU - Nemachek, Craig

AU - Ciborowski, Pawel S

AU - Przedborski, Serge

AU - Mosley, R Lee

AU - Gendelman, Howard Eliot

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Y1 - 2008/1/2

N2 - Background. The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated α-synuclein (N-α-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. Methods and Findings. Nitrotyrosine (NT)-modified α-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 α-Syn. Mice immunized with the NT-modified C-terminal tall fragment of α-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-α-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. Conclusions. These data show that NT modifications within α-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 α-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.

AB - Background. The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated α-synuclein (N-α-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. Methods and Findings. Nitrotyrosine (NT)-modified α-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 α-Syn. Mice immunized with the NT-modified C-terminal tall fragment of α-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-α-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. Conclusions. These data show that NT modifications within α-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 α-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.

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