Extending the functional characteristics of naturally occurring autoantibodies against β-Amyloid, Prion Protein and α-Synuclein

Albus, Alexandra; Gold, Maike; Bach, Jan-Philipp; Burg‐Roderfeld, Monika; Jördens, Marit; Kirchhein, Yvonne; Kronimus, Yannick; Mengel, David; Zerr, Inga; Dodel, Richard

doi:10.1371/journal.pone.0202954

Cited by 10 publications

(9 citation statements)

References 44 publications

(50 reference statements)

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“…We speculate that the increase in anti-αSyn nAb responses is triggered by a higher load of peripheral αSyn in these patients, however, as the high-affinity antibody pool is reduced, this increased IgG1 production may be characterized by a lower affinity profile, resulting in diminished capacity for immune clearance leading to αSyn aggregation. In support of this, it was recently shown that anti-αSyn nAbs present in healthy individuals not only recognize different αSyn structures [ 32 ], but also inhibit the aggregation of αSyn by altering fibril formation in cell culture [ 33 ]. Further, anti-αSyn nAbs isolated from IVIg has shown rescuing effects in both low- and high-dose paradigms in the A53T transgenic PD mice model [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Folke

Bergholt

Pakkenberg

et al. 2022

IJMS

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Multiple-system trophy (MSA) and Parkinson’s Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (αSyn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against αSyn (anti-αSyn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards αSyn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-αSyn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-αSyn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-αSyn IgG-total levels compared to pMSA and controls, concordant with increased anti-αSyn IgG1 levels in pPD. Anti-αSyn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-αSyn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards αSyn occurs prior to disease onset. The apparent lack of high-affinity anti-αSyn nAbs may result in reduced clearance of αSyn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.

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Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Folke

Bergholt

Pakkenberg

et al. 2022

IJMS

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“…Interestingly, nAbs-αSyn are already present in early childhood with levels comparable to healthy adult controls [45]. The binding of nAbs to αSyn monomers, oligomers, and fibrils could be confirmed using dot blot, surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA) [26,46]. nAbs-αSyn purified from commercial intravenous immunoglobulins (IVIG) using αSyn oligomers inhibit aggregation of αSyn as reported by thioflavin T (ThT) fluorescence [26].…”

Section: Introductionmentioning

confidence: 92%

“…nAbs-αSyn were isolated from IVIG as previously described [46]. Briefly, we used purified intravenous immunoglobulin G (IgG) (Gamunex 10%, 100 mg/mL, Grifols, Barclona, Spain).…”

Section: Gravity Flow Affinity Purification Of Nabsmentioning

confidence: 99%

Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo

et al. 2022

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Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD. In this work, we biophysically characterized nAbs against αSyn (nAbs-αSyn) and determined their biological effects. nAbs-αSyn were isolated from commercial intravenous immunoglobulins using column affinity purification. Biophysical properties were characterized using a battery of established in vitro assays. Biological effects were characterized in HEK293T cells transiently transfected with fluorescently tagged αSyn. Specific binding of nAbs-αSyn to monomeric αSyn was demonstrated by Dot blot, ELISA, and Surface Plasmon Resonance. nAbs-αSyn did not affect viability of HEK293T cells as reported by Cell Titer Blue and LDH Assays. nAbs-αSyn inhibited fibrillation of αSyn reported by the Thioflavin T aggregation assay. Altered fibril formation was confirmed with atomic force microscopy. In cells transfected with EGFP-tagged αSyn we observed reduced formation of aggresomes, perinuclear accumulations of αSyn aggregates. The results demonstrate that serum of healthy individuals contains nAbs that specifically bind αSyn and inhibit aggregation of αSyn in vitro. The addition of nAbs-αSyn to cultured cells affects intracellular αSyn aggregates. These findings help understanding the role of the innate immune systems for the pathogenesis of PD and suggest that systemic αSyn binding agents could potentially affect neuronal αSyn pathology.

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“…This changed the concentration of other IgG in the samples, which might influence the binding characteristics of nAbs-α-Syn in the SPR experiments. Importantly, we identified a unique α-Syn bond using nAbs-α-Syn, and no further IgG in these samples seemed to detect the epitope [ 17 ].…”

Section: Limitation Of the Studymentioning

confidence: 99%

The Avidity of Autoreactive Alpha-Synuclein Antibodies in Leucine-Rich Repeat Kinase 2 Mutation Carriers Is Not Altered Compared to Healthy Controls or Patients with Parkinson’s Disease

Albus,

Kronimus,

Burg-Roderfeld

et al. 2023

Biomolecules

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The accumulation and aggregation of alpha-synuclein (α-Syn) are pathological processes associated with Parkinson’s disease, indicating that the regulation of protein is a crucial etiopathological mechanism. Interestingly, human serum and cerebrospinal fluid contain autoantibodies that recognize α-Syn. This potentially demonstrates an already existing, naturally decomposing, and protective system. Thus, quantitative or qualitative alterations, such as the modified antigen binding of so-called naturally occurring autoantibodies against α-Syn (nAbs-α-Syn), may induce disease onset and/or progression. We investigated the serum titers and binding characteristics of nAbs-α-Syn in patients suffering from sporadic Parkinson’s disease (n = 38), LRRK2 mutation carriers (n = 25), and healthy controls (n = 22). Methods: Titers of nAbs-α-Syn were assessed with ELISA and binding affinities and kinetics with SPR. Within the patient cohort, we discriminated between idiopathic and genetic (LRRK2-mutated) variants. Results: ELISA experiments revealed no significant differences in nAbs-α-Syn serum titers among the three cohorts. Moreover, the α-Syn avidity of nAbs-α-Syn was also unchanged. Conclusions: Our findings indicate that nAbs-α-Syn concentrations or affinities in healthy and diseased persons do not differ, independent of mutations in LRRK2.

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Extending the functional characteristics of naturally occurring autoantibodies against β-Amyloid, Prion Protein and α-Synuclein

Cited by 10 publications

References 44 publications

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo

The Avidity of Autoreactive Alpha-Synuclein Antibodies in Leucine-Rich Repeat Kinase 2 Mutation Carriers Is Not Altered Compared to Healthy Controls or Patients with Parkinson’s Disease

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