Journal Article

Nitrated α–Synuclein Immunity Accelerates Degeneration of Nigral Dopaminergic Neurons

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

2008

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology / Adaptive immunity / Adoptive Transfer / alpha-Synuclein - immunology / alpha-Synuclein - metabolism / Animals / Antibodies / Antigen presentation / Antigen-presenting cells / Antigens / Biology / Cell Biology/Neuronal and Glial Cell Biology / Cells, Cultured / Degeneration / Disease / Dopamine receptors / Drug dosages / Enzyme-Linked Immunosorbent Assay / Epitopes / Epitopes - immunology / Flow Cytometry / Immune response / Immune system / Immunity / Immunization / Immunoglobulins / Immunohistochemistry / Immunological tolerance / Immunology / Immunology/Immunomodulation / Immunology/Innate Immunity / Inclusions / Informatics / Leukocytes / Lewy bodies / Life sciences / Lymph nodes / Lymphocytes / Lymphocytes B / Lymphocytes T / Lymphoid tissue / Machinery and equipment / Major histocompatibility complex / Male / Medical treatment / Mice / Mice, Inbred C57BL / Molecular machines / Movement disorders / MPTP / Nervous system / Neurodegeneration / Neurodegenerative diseases / Neurological Disorders/Movement Disorders / Neurons / Neurons - pathology / Neuroscience/Neurobiology of Disease and Regeneration / Neurosciences / Nitrates - metabolism / Nitrotyrosine / Parkinson's disease / Pathogenesis / Pathology / Peptides / Pharmacology / Proteins / Robustness / Rodents / Substantia nigra / Substantia Nigra - drug effects / Substantia Nigra - pathology / Synuclein