Dysregulation of peripheral monocytes and pro-inflammation of alpha-synuclein in Parkinson's disease

J Neurol. 2022 Dec;269(12):6386-6394. doi: 10.1007/s00415-022-11258-w. Epub 2022 Jul 27.


Background and objectives: Mounting evidence indicates the involvement of the innate immune system in Parkinson's disease (PD). Nevertheless, the implications of peripheral monocytes have not been fully elucidated. Although alpha-synuclein (α-synuclein) has been described as a pathological hallmark of PD, the proinflammatory effect of α-synuclein on monocytes is understudied. This study aimed to comprehensively characterize peripheral monocytes in PD patients and to investigate the proinflammatory magnitude of fibrillar α-synuclein.

Methods: Using flow cytometry, we explored the distribution of monocytic subpopulations. We also investigated the actions of peripheral monocytes in response to lipopolysaccharides (LPS) and to fibrillar α-synuclein stimuli by measuring inflammatory molecule levels in post-culture supernatants.

Results: Classical monocytes were enriched, in parallel with lower proportions of intermediate and nonclassical monocytes in patients with PD than in controls. Lower levels of TNF-α and IL-6 were spontaneously produced by unstimulated monocytes in patients with PD. LPS and fibrillar α-synuclein stimuli induced high levels of TNF-α, IL-1β, IL-6, and sCD163 in the PD and control groups. Strikingly, the fold induction of TNF-α and IL-6 was lower in patients with PD than that in normal controls under the same stimulation.

Conclusion: Our results revealed a strong dysregulation of peripheral monocytes in PD patients, including subpopulation shifts and impaired response to specific stimuli, and the proinflammatory effect of α-synuclein on monocytes. Further studies are needed to clarify the specific mechanisms by which these immunological abnormalities are present in PD to open the possibility of immunoregulatory therapy.

Keywords: Alpha-synuclein; Innate immune system; Parkinson’s disease; Peripheral monocytes.

MeSH terms

  • Cytokines
  • Humans
  • Inflammation
  • Interleukin-6
  • Lipopolysaccharides / pharmacology
  • Monocytes / pathology
  • Parkinson Disease* / pathology
  • Tumor Necrosis Factor-alpha
  • alpha-Synuclein*


  • alpha-Synuclein
  • Lipopolysaccharides
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Cytokines