Effect of naturally occurring α-synuclein-antibodies on toxic α-synuclein-fragments. (21st June 2019)

• Record Type: Journal Article
• Authors: Rabenstein, Monika; Besong Agbo, Daniela; Wolf, Elias; Dams, Judith; Nicolai, Marina; Roeder, Andreas; Bacher, Michael; Dodel, Richard C.; Noelker, Carmen
• Is Part Of: Neuroscience letters. Volume 704(2019)
• Page Start: 181
• Page End: 188
• Publication Date: 2019-06-21
• Subjects: AA amino acid residues -- Ab Antibody -- α-Syn alpha-synuclein -- ANOVA One Way Analysis of Variance -- CNS central nervous system -- CSF cerebrospinal fluid -- DMSO dimethyl sulfoxide -- FT Abs flow-through antibodies (IVIG depleted of nAbs α-Syn) -- IgG immunoglobulin G -- IL-6 interleukin-6 -- IVIG intravenous immunoglobulins -- LB Lewy bodies -- mAb α-Syn monoclonal antibody against α-Syn -- MTT 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide -- nAbs naturally occurring autoantibodies -- nAbs α-Syn naturally occurring autoantibodies against α-Syn -- PBS phosphate-buffered saline -- PD Parkinson's disease -- SNCA α-Syn-encoding gene -- TNF-α tumor necrosis factor alpha; Alpha-synuclein -- Immunotherapy -- Inflammation -- IVIG -- Microglia -- Naturally occurring antibodies -- Parkinson's disease; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2019.04.004
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Naturally occurring autoantibodies against human α-Syn (nAbs α-Syn) were detected in the peripheral blood of PD patients and controls in different levels. We investigated the inhibitory effect of nAbs α-Syn on distinct α-Syn fragments induced inflammation and cytotoxicity on pr0imary microglia. All α-Syn fragments induced the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) from primary cultured microglia. Cotreatment with nAbs α-Syn did alleviate the release of pro-inflammatory cytokines induced by the α-Syn fragments α-Syn 1–95, α-Syn 61–140, α-Syn 96–140 and α-Syn 112. Treatment with the α-Syn fragments α-Syn 1–95, α-Syn 61–140 and α-Syn 112 impaired the viability of primary microglia. This effect could not be counteracted by cotreatment with nAbs α-Syn. Abstract: Alpha-synuclein (α-Syn) is a soluble protein primarily expressed in presynaptic terminals in the central nervous system (CNS). Aggregates of fibrillated α-Syn are the major component of Lewy bodies (LB), a pathologic hallmark of idiopathic Parkinson's disease (PD). Recently, naturally occurring autoantibodies against human α-Syn (nAbs α-Syn) were detected in the peripheral blood of PD patients and controls. Here, we investigated the inhibitory effects of nAbs α-Syn on distinct α-Syn fragments, as well as inflammatory responses and cytotoxicity evoked by nAbs α-Syn in primary microglia. All α-Syn fragments induced the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) from microglia in primary culture. Cotreatment with nAbs α-Syn alleviated the release of pro-inflammatory cytokines induced by α-Syn fragments α-Syn 1–95, α-Syn 61–140, α-Syn 96–140 and α-Syn 112. Treatment with the α-Syn fragments α-Syn 1–95, α-Syn 61–140 and α-Syn 112 impaired the viability of primary microglia. This effect could not be counteracted by cotreatment with nAbs α-Syn. Data suggest an important role of nAbs α-Syn in the α-Syn-induced inflammation cascade, and indicate the potential importance of nAbs in the pathogenesis of PD. This could provide an experimental therapeutic target for patients with PD.