Autoantibodies to alpha-synuclein in inherited Parkinson’s disease (original) (raw)
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An impedimetric assay of α-synuclein autoantibodies in early stage Parkinson's disease
a-Synuclein (a-Syn), a protein synthesized by neurons, as the major protein component of Lewy body inclusions, undoubtedly has a prominent role in the pathogenesis of Parkinson's Disease (PD). In an attempt to enable pre-symptomatic and definitive diagnosis, numerous attempts have been made to align assayed total a-Syn levels in serum (where there is a native presence) to PD disease status. Results have been conflicting. The status of circulating and potentially neuroprotective a-Syn autoantibodies in PD subjects is also unclear. In previous work we demonstrated that electrochemically assayed autoantibody levels were higher in PD patients compared to controls and, significantly, noted that this differentiation was most marked early in disease. Herein we report a robust (coefficient of variation 3.0%) single step and label free analysis of 90 subjects, including 60 PD patients, with a mean disease duration of 1.4 years and 29 control subjects. In this cross sectional cohort we observe a statistically significant (p < 0.05; Mann-Whitney U test) difference in autoantibody levels in PD patients versus controls, although there was no resolved scaling with symptomatic disease stage (p > 0.05; Kruskal-Wallis test).
Frontiers in neurology, 2017
Early diagnosis of neurodegenerative diseases is of paramount importance for successful treatment. Lack of sensitive and early biomarkers for diagnosis of diseases like Parkinson's disease (PD) is a handicapping problem for all movement disorders specialists. Using serum autoimmune antibodies (AIAs) against neural proteins is a new promising strategy to diagnose brain disorders through non-invasive and cost-effective method. In the present study, we measured the level of AIAs against α-synuclein (α-syn), which is an important protein involved in the pathogenesis of PD. In our study patients with PD (46 patients), Alzheimer's disease (AD) (27 patients) and healthy controls (20 patients) were evaluated according to their sera α-syn AIAs levels. Interestingly, α-syn AIAs were significantly elevated in PD group compared to AD and healthy controls, which advocates their use for diagnosis of PD.
ACS chemical neuroscience, 2017
Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, α-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis. We found significantly elevated levels of α-synuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of α-synuclein antibodies in both plasma and CSF. For the first time, we showed the correlation between plasma and CSF α-synuclein antibody levels for mild, moderate, and combined PD groups. This in...
PLoS ONE, 2013
Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of a-synuclein due to genetic multiplication or point mutations leads to early onset disease. While a-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of a-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC a-synuclein transgenic mice, which overexpress a-synuclein under regulation of its own promoter, express a-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure a-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of a-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal a-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased a-synuclein and altered phagocytosis may provide a useful biomarker for human PD. PLOS ONE | www.plosone.org August 2013 | Volume 8 | Issue 8 | e71634 a-Syn Impedes Innate Immune Activity PLOS ONE | www.plosone.org 2 August 2013 | Volume 8 | Issue 8 | e71634
Journal of neurochemistry, 2018
Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared to HC, whereas serum levels were not significantly different. CSF auto-antibody levels did n...
Increased immune activation by pathologic alpha‐synuclein in Parkinson's Disease
Annals of Neurology
Objective: Excessive inflammation in the CNS and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson"s disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although alpha-synuclein pathology is the hallmark of Parkinson"s disease, it has not been investigated if pathologic alpha-synuclein is a specific trigger for excessive inflammatory responses in Parkinson"s disease. Methods: We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of alpha-synuclein by assessing cytokine release upon exposure. Results: We show that pathologic alpha-synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation-dependent, with increasing fibrillation and early-onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular alpha-synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of alpha-synuclein. Blood extracellular vesicles from Parkinson"s disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson"s disease patients are dysregulated and hyperactive in response to stimulation with pathologic alpha-synuclein. Furthermore, we demonstrate that α-syn pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model. Interpretation: Taken together, our data suggests that alpha-synuclein pathology and dysregulation of monocytes in Parkinson"s disease can act together to induce excessive inflammatory responses to alpha-synuclein.
PLoS ONE, 2011
Background: Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments.
Microglia Response During Parkinson's Disease: Alpha-Synuclein Intervention
Frontiers in cellular neuroscience, 2018
The discovery of the central role played by the protein alpha-synuclein in Parkinson's disease and other Lewy body brain disorders has had a great relevance in the understanding of the degenerative process occurring in these diseases. In addition, during the last two decades, the evidence suggesting an immune response in Parkinson's disease patients have multiplied. The role of the immune system in the disease is supported by data from genetic studies and patients, as well as from laboratory animal models and cell cultures. In the immune response, the microglia, the immune cell of the brain, will have a determinant role. Interestingly, alpha-synuclein is suggested to have a central function not only in the neuronal events occurring in Parkinson's disease, but also in the immune response during the disease. Numerous studies have shown that alpha-synuclein can act directly on immune cells, such as microglia in brain, initiating a sterile response that will have consequence...