Immune responses to oligomeric α-synuclein in Parkinson’s disease peripheral blood mononuclear cells

• Published in: Journal of neurology Vol. 271; no. 9; pp. 5916 - 5929
• Main Authors: Vega-Benedetti, Ana Florencia, Porcedda, Clara, Ercoli, Tommaso, Fusco, Giuliana, Burgaletto, Chiara, Pillai, Rita, Palmas, Francesca, Cantone, Anna Flavia, Angius, Fabrizio, Solla, Paolo, De Simone, Alfonso, Cantarella, Giuseppina, Giallongo, Cesarina, Sogos, Valeria, Defazio, Giovanni, Carta, Anna R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2024; Springer Nature B.V
• Subjects: Aged; alpha-Synuclein - blood; alpha-Synuclein - immunology; Basal ganglia; Cell culture; Central nervous system; Central nervous system diseases; Chemokines; Constipation; Correlation analysis; Cytokines; Cytokines - blood; Cytokines - immunology; Cytokines - metabolism; Female; Flow cytometry; Genotype & phenotype; Humans; Immune response; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Male; Medicine; Medicine & Public Health; Middle Aged; Monomers; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurology; Neuroradiology; Neurosciences; Oligomers; Original Communication; Parkinson Disease - blood; Parkinson Disease - immunology; Parkinson's disease; Pathology; Peripheral blood mononuclear cells; Phenotypes; Synuclein; constipation; monocytes; olfaction; cytokines; PBMC; natural killers
• ISSN: 0340-5354; 1432-1459; 1432-1459
• DOI: 10.1007/s00415-024-12554-3

Parkinson’s disease displays clinical heterogeneity, presenting with motor and non-motor symptoms. Heterogeneous phenotypes, named brain-first and body-first, may reflect distinct α-synuclein pathology starting either in the central nervous system or in the periphery. The immune system plays a prominent role in the central and peripheral pathology, with misfolded α-synuclein being placed at the intersection between neurodegeneration and inflammation. Here, we characterized the inflammatory profile and immune-phenotype of peripheral blood mononuclear cells (PBMCs) from Parkinson’s disease patients upon stimulation with α-synuclein monomer or oligomer, and investigated relationships of immune parameters with clinical scores of motor and non-motor symptoms. Freshly isolated PBMCs from 21 Parkinson’s disease patients and 18 healthy subjects were exposed in vitro to α-synuclein species. Cytokine/chemokine release was measured in the culture supernatant by Multiplex Elisa. The immune-phenotype was studied by FACS-flow cytometry. Correlation analysis was computed between immune parameters and parkinsonian motor and non-motor scales. We found that Parkinson’s disease patients exhibited a dysregulated PBMC-cytokine profile, which remained unaltered after exposure to α-synuclein species and correlated with both motor and non-motor severity, with a strong correlation observed with olfactory impairment. Exposure of PBMCs from healthy controls to α-synuclein monomer/oligomer increased the cytokine/chemokine release up to patient’s values. Moreover, the PBMCs immune phenotype differed between patients and controls and revealed a prominent association of the Mos profile with olfactory impairment, and of NK profile with constipation. Results suggest that a deranged PBMC-immune profile may reflect distinct clinical subtypes and would fit with the recent classification of Parkinson’s disease into peripheral-first versus brain-first phenotype.