Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease

PLoS One. 2013 Aug 23;8(8):e71634. doi: 10.1371/journal.pone.0071634. eCollection 2013.

Abstract

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Cells, Cultured
  • Cytokines / immunology
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Immunity, Innate*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Microglia / immunology
  • Microglia / metabolism
  • Microglia / pathology
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism
  • Monocytes / pathology
  • Parkinson Disease / diagnosis*
  • Parkinson Disease / genetics
  • Parkinson Disease / immunology*
  • Parkinson Disease / pathology
  • Phagocytosis
  • Up-Regulation
  • alpha-Synuclein / genetics
  • alpha-Synuclein / immunology*

Substances

  • Cytokines
  • alpha-Synuclein

Grant support

All authors were employees of either Elan Pharmaceuticals or The Parkinson's Institute. Work accomplished at Elan was supported by Elan Pharmaceuticals. B. Shulle, J. Langston, and S. Kim were supported by Parkinson Alliance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.