Naturally occurring autoantibodies against α-synuclein rescues memory and motor deficits and attenuates α-synuclein pathology in mouse model of Parkinson's disease

Huang, Yaru; Xie, Xin; Ji, Mei; Yu, Xiaolin; Zhu, Jie; Zhang, Lingxiao; Liu, Xiao-Ge; Chen, Wei; Li, Gang; Liu, Rui‐tian

doi:10.1016/j.nbd.2018.11.024

Cited by 24 publications

(24 citation statements)

References 54 publications

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“…NAb-α-Syn may aid in the clearance of α-Syn, resulting in the alleviation of neuronal injury by α-Syn. This hypothesis is supported by previous studies, which suggests that NAb-α-Syn rescues memory and motor functions and attenuates α-Syn pathologies in animal models of PD (Huang et al, 2019). In this regard, NAb-α-Syn might be a physiological protective factor against α-Syn pathologies.…”

Section: Discussionsupporting

confidence: 81%

Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson’s Disease Dementia, Alzheimer’s Disease, and Vascular Dementia

Wang¹,

Zheng²,

Yang

et al. 2020

Front. Aging Neurosci.

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Background: Aggregation of alpha-synuclein (α-Syn) is considered to be a significant pathological hallmark and a driving force of Parkinson's disease (PD). PD dementia (PDD) occurs in a substantial number of PD patients. Naturally occurring antibody against α-Syn (NAb-α-Syn) exists ubiquitously in human blood and is reported to be altered in PD. However, it is not clear yet whether PDD had similar changes of circulating NAb-α-Syn. Methods: In this study, we recruited 61 PDD patients, 52 patients with Alzheimer's disease (AD), 51 patients with vascular dementia (VaD), and 50 normal controls (NCs). ELISA was used to examine NAb-α-Syn levels in serum. Results: In comparison with NCs, serum levels of NAb-α-Syn were significantly lower in patients with PDD. However, serum levels of NAb-α-Syn were comparable among AD, VaD, and NC groups. Serum levels of NAb-α-Syn were positively correlated with the cognitive function, as reflected by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Serum levels of NAb-α-Syn were negatively correlated with the severity of PD [as reflected by the Unified Parkinson Disease Rating Scale (UPDRS)] and the duration of PD and PDD. Serum NAb-α-Syn can differentiate PDD patients from AD and VaD patients. Conclusion: These results suggest that circulating NAb-α-Syn might be a potential biomarker of PDD.

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Section: Discussionsupporting

confidence: 81%

Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson’s Disease Dementia, Alzheimer’s Disease, and Vascular Dementia

Wang¹,

Zheng²,

Yang

et al. 2020

Front. Aging Neurosci.

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“…Patients suffering from neurodegenerative conditions exhibit T cell- and/or antibody-mediated responses directed against major neurodegeneration-associated proteins such as amyloid beta A4 protein, alpha-synuclein and tau protein (4–6, 73). However, naturally-occurring antibodies against amyloid-beta (74), alpha-synuclein (75–77) and tau protein (73, 77, 78) were also demonstrated in cohorts of healthy subjects. Similarly, apart from any pathological context, robust T-cell responses against peptides deriving from tau protein were recently demonstrated to widely occur in the general population (79).…”

Section: Discussionmentioning

confidence: 99%

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

2019

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There is circumstantial evidence that, under neurodegenerative conditions, peptides deriving from aggregated or misfolded specific proteins elicit adaptive immune responses. On another hand, several genes involved in familial forms of neurodegenerative diseases exert key innate immune functions. However, whether or not such observations are causally linked remains unknown. To start addressing this issue, we followed a systems biology strategy based on the mining of large proteomics and immunopeptidomics databases. First, we retrieved the expression patterns of common neurodegeneration-associated proteins in two professional antigen-presenting cells, namely B lymphocytes and dendritic cells. Surprisingly, we found that under physiological conditions, numerous neurodegeneration-associated proteins are abundantly expressed by human B lymphocytes. A survey of the human proteome allowed us to map a unique protein-protein interaction network linking common neurodegeneration-associated proteins and their first shell interactors in human B lymphocytes. Interestingly, network connectivity analysis identified two major hubs that both relate with inflammation and autophagy, namely TRAF6 (TNF Receptor Associated Factor 6) and SQSTM1 (Sequestosome-1). Moreover, the mapped network in B lymphocytes comprised two additional hub proteins involved in both inflammation and autoimmunity: HSPA8 (Heat Shock Protein Family A Member 8 also known as HSC70) and HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1). Based on these results, we then explored the Immune Epitope Database “IEDB-AR” and actually found that a large share of neurodegeneration-associated proteins were previously reported to provide endogenous MHC class II-binding peptides in human B lymphocytes. Of note, peptides deriving from amyloid beta A4 protein, sequestosome-1 or profilin-1 were reported to bind multiple allele-specific MHC class II molecules. In contrast, peptides deriving from microtubule-associated protein tau, presenilin 2 and serine/threonine-protein kinase TBK1 were exclusively reported to bind MHC molecules encoded by the HLA-DRB1 1501 allele, a recently-identified susceptibility gene for late onset Alzheimer's disease. Finally, we observed that the whole list of proteins reported to provide endogenous MHC class II-binding peptides in human B lymphocytes is specifically enriched in neurodegeneration-associated proteins. Overall, our work indicates that immunization against neurodegeneration-associated proteins might be a physiological process which is shaped, at least in part, by B lymphocytes.

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“…The pathological changes associated with PD might contribute to the levels of naturally occurring α-syn autoantibodies in both serum and CSF. Both of these are potential biomarkers for PD patients [ 128 , 129 ]. However, studies of α-syn antibodies report inconsistent measurements of antibody levels.…”

Section: Role Of Igs In Pdmentioning

confidence: 99%

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

Sim

Park

2020

IJMS

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Natural autoantibodies, immunoglobulins (Igs) that target self-proteins, are common in the plasma of healthy individuals; some of the autoantibodies play pathogenic roles in systemic or tissue-specific autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, the field of autoantibody-associated diseases has expanded to encompass neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), with related studies examining the functions of Igs in the central nervous system (CNS). Recent evidence suggests that Igs have various effects in the CNS; these effects are associated with the prevention of neurodegeneration, as well as induction. Here, we summarize the functional roles of Igs with respect to neurodegenerative disease (AD and PD), focusing on the target antigens and effector cell types. In addition, we review the current knowledge about the roles of these antibodies as diagnostic markers and immunotherapies.

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Naturally occurring autoantibodies against α-synuclein rescues memory and motor deficits and attenuates α-synuclein pathology in mouse model of Parkinson's disease

Cited by 24 publications

References 54 publications

Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson’s Disease Dementia, Alzheimer’s Disease, and Vascular Dementia

Differential Circulating Levels of Naturally Occurring Antibody to α-Synuclein in Parkinson’s Disease Dementia, Alzheimer’s Disease, and Vascular Dementia

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

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