Inflammatory Responses to Monomeric and Aggregated α-Synuclein in Peripheral Blood of Parkinson Disease Patients.

Federica Piancone,Francesca La Rosa,Mario Meloni,Mario Clerici,Marina Saresella,Ivana Marventano,Jorge Navarro

doi:10.3389/fnins.2021.639646

Federica Piancone, Francesca La Rosa + Show 5 more

Open Access

https://doi.org/10.3389/fnins.2021.639646

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Abstract

To investigate whether different forms of α-synuclein (α-syn) proteins can induce inflammation and activate the NLRP3 inflammasome, we stimulated with monomeric or aggregated α-syn peripheral blood mononuclear cells of Parkinson disease (PD) patients and age- and sex-matched healthy controls (HC). ASC-speck formation, i.e., the intracellular generation of functionally active inflammasome complexes, as well as the production of inflammasome-related [caspase-1, interleukin 1β (IL-18), and IL-1β], and pro–IL-6, or anti–IL-10 inflammatory cytokines were evaluated. Gastrointestinal permeability, suggested to be altered in PD, was also investigated by measuring plasma concentration of lipopolysaccharide (LPS) and I-FABP (fatty acid–binding protein). ASC-speck expression, as well as IL-18 and caspase-1 production and LPS and I-FABP plasma concentration, was comparable in PD and HC, indicating that α-syn does not stimulate the NLRP3 inflammasome and that PD does not associate with alterations of intestinal permeability. Interestingly, though, IL-1β and IL-6 production was increased, whereas that of IL-10 was reduced in α-syn–stimulated cells of PD compared to HC, suggesting that PD-associated neuroinflammation is not the consequence of the activation of the NLRP3 inflammasome but rather of an imbalance between proinflammatory and anti-inflammatory cytokines.

Highlights

IntroductionParkinson disease (PD) is an age-related neurodegenerative disorder (Rodriguez et al, 2015) characterized by motor (bradykinesia, muscular rigidity, rest tremor, and postural and gait impairment) and non-motor symptoms (including cognitive impairment, psychiatric symptoms, sleep disorders, autonomic dysfunction, pain, and fatigue)
Parkinson disease (PD) is an age-related neurodegenerative disorder (Rodriguez et al, 2015) characterized by motor and non-motor symptoms
Whereas no differences were observed in tumor necrosis factor α (TNF-α) (Figure 6), IL-6 production was significantly increased in healthy controls (HC) compared to PD in Peripheral blood mononuclear cells (PBMCs) stimulated with either monomeric (HC = 3,071.2 pg/mL; PD = 2,341.5 pg/mL) (p = 0.008) or aggregated (HC = 2,821.3 pg/mL; PD = 2,031.2 pg/mL) (p = 0.01) α-syn (Figure 7)

Summary

Introduction

Parkinson disease (PD) is an age-related neurodegenerative disorder (Rodriguez et al, 2015) characterized by motor (bradykinesia, muscular rigidity, rest tremor, and postural and gait impairment) and non-motor symptoms (including cognitive impairment, psychiatric symptoms, sleep disorders, autonomic dysfunction, pain, and fatigue). All these are thought to be the result, among others, of the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain (Ruiperez et al, 2010). This observation, together with the experimental evidences that (1) abnormal forms of α-syn can be observed in enteric nerves before they appear in the brain (Corbillé et al, 2016), and (2) abnormal α-syn injected into the wall of the intestine spreads to the vagus nerve (Holmqvist et al, 2014), led to the hypothesis that PD may initiate in the gut

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