Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells

Author(s): Reynolds AD, Stone DK, Mosley RL, Gendelman HE

Abstract

Microglial inflammatory responses affect Parkinson's disease (PD) associated nigrostriatal degeneration. This is triggered, in measure, by misfolded, nitrated alpha-synuclein (N-alpha-syn) contained within Lewy bodies that are released from dying or dead dopaminergic neurons into the extravascular space. N-alpha-syn-stimulated microglial immunity is regulated by CD4+ T cell subset. Indeed, CD4+CD25+ regulatory T cells (Treg) induce neuroprotective immune responses. This is seen in rodent models of stroke, amyotrophic lateral sclerosis, human immunodeficiency virus associated neurocognitive disorders, and PD. To elucidate the mechanism for Treg-mediated microglial neuroregulatory responses, we used a proteomic platform integrating difference gel electrophoresis and tandem mass spectrometry peptide sequencing. These tests served to determine consequences of Treg on the N-alpha-syn stimulated microglia. The data demonstrated that Treg substantially alter the microglial proteome in response to N-alpha-syn. This is seen through Treg abilities to suppress microglial proteins linked to cell metabolism, migration, protein transport and degradation, redox biology, cytoskeletal, and bioenergetic activities. We conclude that Treg modulate the N-alpha-syn microglial proteome and, in this way, can slow the tempo and course of PD.

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