Α-synuclein Peptides Research Articles

Exploring α-synuclein stability under the external electrostatic field: Effect of repeat unit

Parkinson’s disease (PD) is a category of neurodegenerative disorders (ND) that currently lack comprehensive and definitive treatment strategies. The etiology of PD can be attributed to the presence and aggregation of a protein known as α-synuclein. Researchers have observed that the application of an external electrostatic field holds the potential to induce the separation of the fibrous structures into peptides. To comprehend this phenomenon, our investigation involved simulations conducted on the α-synuclein peptides through the application of Molecular Dynamics (MD) simulation techniques under the influence of a 0.1 V/nm electric field. The results obtained from the MD simulations revealed that in the presence of external electric field, the monomer and oligomeric forms of α-synuclein are experienced significant conformational changes which could prevent them from further aggregation. However, as the number of peptide units in the model system increases, forming trimers and tetramers, the stability against the electric field also increases. This enhanced stability in larger aggregates indicates a critical threshold in α-synuclein assembly where the electric field’s effectiveness in disrupting the aggregation diminishes. Therefore, our findings suggest that early diagnosis and intervention could be crucial in preventing PD progression. When α-synuclein predominantly exists in its monomeric or dimeric form, applying even a lower electric field could effectively disrupt the initial aggregation process. Inhibition of α-synuclein fibril formation at early stages might serve as a viable solution to combat PD by halting the formation of more stable and pathogenic α-synuclein fibrils.

A candidate reference measurement procedure for the quantification of α-synuclein in cerebrospinal fluid using an SI traceable primary calibrator and multiple reaction monitoring.

α-synuclein aggregation is an important hallmark of neurodegenerative diseases such as Parkinson's disease (PD) and Lewy body dementia. α-synuclein has been increasingly used as a diagnostic biomarker in PD and other synucleinopathies. Current clinical assays rely on antibody-based immunoassays to detect α-synuclein, which possess high sensitivity, afford high throughput and require small sample volumes. The utility of these assays, however, may be compounded by the specificity, selectivity and batch-to-batch heterogeneity of the antibody used, which can lead to deviations in the total amount of the protein measured when comparing results among different laboratories. Similarly, current mass spectrometry-based quantification methods for α-synuclein lack well-defined, value assigned calibrators to ensure comparability of measurements. Therefore, there is still an unmet need for the standardisation of clinical measurements for α-synuclein that can be achieved by the development of reference measurement procedures (RMPs) utilising calibrators traceable to the SI (International System of Units). Here, we report a candidate RMP for α-synuclein, using an SI traceable primary calibrator and an isotope dilution mass spectrometry (IDMS) approach to address this need. The gravimetrically prepared primary calibrator was traceably quantified utilising a combination of amino acid analysis (AAA) and quantitative nuclear magnetic resonance (qNMR) for value assignment. An optimised targeted sample clean-up procedure involving a non-denaturing Lys-C digestion and solid-phase extraction strategy was devised, followed by the development of a targeted multiple reaction monitoring (MRM) method for the quantification of α-synuclein in cerebrospinal fluid (CSF). This candidate RMP was then deployed for the sensitive detection and accurate quantification of multiple proteotypic α-synuclein peptides in patient derived CSF samples. The LC-MS based results were subsequently compared to immunoassay data to assess the overall performance of our approach. The development and adoption of this candidate RMP, along with the availability of the SI traceable primary calibrator will allow for reliable quantifications of α-synuclein in CSF by an LC-MS based assay. The RMP will potentially contribute towards the standardisation of this important biomarker and may lead to future interlaboratory comparisons.

Deep Learning-Assisted Single-Molecule Detection of Protein Post-translational Modifications with a Biological Nanopore.

Protein post-translational modifications (PTMs) play a crucial role in countless biological processes, profoundly modulating protein properties on both spatial and temporal scales. Protein PTMs have also emerged as reliable biomarkers for several diseases. However, only a handful of techniques are available to accurately measure their levels, capture their complexity at a single molecule level, and characterize their multifaceted roles in health and disease. Nanopore sensing provides high sensitivity for the detection of low-abundance proteins, holding the potential to impact single-molecule proteomics and PTM detection, in particular. Here, we demonstrate the ability of a biological nanopore, the pore-forming toxin aerolysin, to detect and distinguish α-synuclein-derived peptides bearing single or multiple PTMs, namely, phosphorylation, nitration, and oxidation occurring at different positions and in various combinations. The characteristic current signatures of the α-synuclein peptide and its PTM variants could be confidently identified by using a deep learning model for signal processing. We further demonstrate that this framework can quantify α-synuclein peptides at picomolar concentrations and detect the C-terminal peptides generated by digestion of full-length α-synuclein. Collectively, our work highlights the advantage of using nanopores as a tool for simultaneous detection of multiple PTMs and facilitates their use in biomarker discovery and diagnostics.

α-Synuclein Drives Tau's Cytotoxic Aggregates Formation through Hydrophobic Interactions.

Tau and α-synuclein are proteins involved in pathologies known as tauopathies and synucleinopathies, respectively. Moreover, evidence shows that there is a crosstalk between them as is seen in the brains of individuals with sporadic neurodegenerative disorders. Based on that, we present data showing that the hydrophobic α-peptide 71 VTGVTAVAQKTV82 induces the aggregation of the full-length tau fragment in the absence of heparin assessed by ThT. Moreover, AFM images reveal the presence of straight filaments and amorphous aggregates of full-length tau in the presence of the α-peptide. Additionally, ITC experiments showed the interaction of the α-peptide with tau full-length (441 amino acids),4R (amino acids from 244 to 369), and both hexapeptides 275 VQIINK280 and 306 VQIVYK311 through hydrophobic interactions. The Raman spectroscopy spectra showed conformational changes in the Amide region in the aggregates formed with full-length tau and α-syn peptide. Furthermore, the incubation of extracellular aggregates with N2a cells showed morphological differences in the cellular body and the nucleus suggesting cell death. Moreover,, the incubation of different types of aggregates in cell culture provokes the release of Lactate dehydrogenase (LDH). Altogether, we found that α-synuclein peptide can drive the aggregation of full-length tau-provoking morphological and structural changes evoking cytotoxic effects.

Monitoring α-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation.

While defective α-synuclein homeostasis is central to Parkinson's pathogenesis, fundamental questions about its degradation remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of α-synuclein and identified lysine residues 45, 58, and 60 as critical ubiquitination sites for its degradation. This is mediated by NBR1 binding and entry into endosomes in a process that involves ESCRT I-III for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 is dispensable for this pathway. Antibodies against diglycine-modified α-synuclein peptides confirmed that endogenous α-synuclein is similarly ubiquitinated in the brain and targeted to lysosomes in primary and iPSC-derived neurons. Ubiquitinated α-synuclein was detected in Lewy bodies and cellular models of aggregation, suggesting that it may be entrapped with endo/lysosomes in inclusions. Our data elucidate the intracellular trafficking of de novo ubiquitinated α-synuclein and provide tools for investigating the rapidly turned-over fraction of this disease-causing protein.

Microscopic Understanding of the Conformational Stability of the Aggregated Nonamyloid β Components of α-Synuclein.

Self-association of α-synuclein peptides into oligomeric species and ordered amyloid fibrils is associated with Parkinson's disease, a progressive neurodegenerative disorder. In particular, the peptide domain formed between the residues Glu-61 (or E61) and Val-95 (or V95) of α-synuclein, typically termed the "nonamyloid β component" (NAC), is known to play critical roles in forming aggregated structures. In this work, we have employed molecular dynamics simulations to explore the conformational properties and relative stabilities of aggregated protofilaments of different orders, namely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)), dodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domains of α-synuclein. Besides, center-of-mass pulling and umbrella sampling simulation methods have also been employed to characterize the mechanistic pathway of peptide association/dissociation and the corresponding free energy profiles. Structural analysis showed that the disordered C-terminal loop and the central core regions of the peptide units lead to more flexible and distorted structures of the lower order protofilaments (P(4) and P(6)) as compared to the higher order ones. Interestingly, our calculation shows the presence of multiple distinctly populated conformational states for the lower order protofilament P(4), which may drive the oligomerization process along multiple pathways to form different polymorphic α-synuclein fibrillar structures. It is further observed that the nonpolar interaction between the peptides and the corresponding nonpolar solvation free energy play a dominant role in stabilizing the aggregated protofilaments. Importantly, our result showed that reduced cooperativity during the binding of a peptide unit beyond a critical size of the protofilament (P(12)) leads to less favorable binding free energy of a peptide.

In Silico Studies to Predict the Role of Solvent in Guiding the Conformations of Intrinsically Disordered Peptides and Their Aggregated Protofilaments.

The formation of amyloids due to the self-assembly of intrinsically disordered proteins or peptides is a hallmark for different neurodegenerative diseases. For example, amyloids formed by the amyloid beta (Aβ) peptides are responsible for the most devastating neuropathological disease, namely, Alzheimer's disease, while aggregation of α-synuclein peptides causes the etiology of another neuropathological disease, Parkinson's disease. Characterization of the intermediates and the final amyloid formed during the aggregation process is, therefore, crucial for microscopic understanding of the origin behind such diseases, as well as for the development of proper therapeutics to combat those. However, most of the research activities reported in this area have been directed toward examining the early stages of the aggregation process, including probing the conformational characteristics of the responsible protein/peptide in the monomeric state or in small oligomeric forms. This is because the small soluble oligomers have been found to be more deleterious than the final insoluble amyloids. This review discusses some of the recent findings obtained from our simulation studies on Aβ and α-synuclein monomers and small preformed Aβ aggregates. A molecular-level insight of the aggregation process with a special emphasis on the role of water in inducing the aggregation process has been provided.

Computational Modeling of the Effect of Trifluoroethanol on the Conformation of α-Synuclein Peptide

Alpha-Synuclein is a presynaptic neuronal protein whose masses are involved in Parkinson’s disease, a chronic and progressive neurodegenerative disorder of the central nervous system. It has been observed that upon exposure to anionic surfactants, fluorinated alcohols and membranes in vitro, [Formula: see text]-synuclein adopts alpha helix structure and can be fibrillated, while in aqueous solution, the protein is intrinsically disordered and the fibrillation is undesirable. Solvent is one of the most critical environmental parameters in biological studies as well as computer simulations. In this paper, we have investigated the effect of solvent composition on the conformation of [Formula: see text]-synuclein protein using molecular dynamics (MD) simulations. For this purpose, the effect of different combinations of water and trifluoroethanol (TFE) solvents on the secondary structure of a fragment of [Formula: see text]-synuclein was investigated. Moreover, thermodynamic calculations were performed through a coarse-grained (CG) model of solutions with different concentrations of [Formula: see text]-synuclein in the aqueous phase and in TFE medium. The potential of mean force (PMF) calculations was performed as a function of separation distance between the centers of masses of two peptides. The results indicated that in the presence of TFE, the secondary structures have a regular arrangement of amino acids stabilized by hydrogen bonding patterns. In addition, decreasing the TFE concentration reduces the stability of [Formula: see text]-helix structures of the protein. It seems that in diluted TFE solutions, high concentrations of water in the medium lead to the breakage of peptide–TFE hydrogen bonds. However, the hydrophobic nature of TFE and [Formula: see text]-synuclein molecules prevents further aggregation in the concentrated solutions.

Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele

The amygdala is vulnerable to multiple or "mixed" mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementia-associated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer's Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/Aβ, and α-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE ε4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE ε3/ε3 subjects' amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an "upstream" genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE ε4 allele.

Electrochemical approach for the aptamer-like conformational changes of α-synuclein peptides in the presence of copper(II)

The structure and aggregation states of alpha-synuclein (α-syn) have been shown to have a connection to the pathological development of Parkinson's disease (PD). Computational modeling studies have indicated that α-syn proteins misfold in the presence of biometals such as copper, iron and zinc, resulting in down-stream off-pathway oligomerization. If the early folding processes can be prevented, subsequent neurotoxicity due to the production of reactive oxygen species induced by the formation of α-syn-Cu(II) complexes can be suppressed. However, experimental data are lacking to support this hypothesis and many traditional approaches lack speed and sample volume efficiency. Through the application of an aptamer-like folding/unfolding strategy on an electrochemical platform, these challenges can be resolved. By exploiting the effect of spatial distance between the redox probe and electrode surface, a biosensor capable of monitoring the structural changes of α-syn peptides was constructed. Ferrocene-conjugated α-syn peptides (Fc-PEP) were immobilized on gold surfaces via gold-sulfur bond. Square-wave voltammetry (SWV) was used to monitor the Fc oxidation signal in the presence and absence of Cu(II). Full surface characterization studies were performed using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The results showed that Fc-PEPs folded in the presence of Cu(II), and this behaviour could be reversed with the addition of EDTA. The biosensor was able to demonstrate distinguishable current responses between the effects of Cu(II) and Zn(II) on the folding of Fc-PEPs. Finally, in the presence of a well-described antioxidant and amyloid inhibitor, pyrroloquinoline quinone (PQQ), the current responses remained the same, indicating the strong interaction between PQQ and Fc-PEPs that suppressed the folding process. Our preliminary results demonstrated that an aptamer-like electrochemical approach has a promising potential for developing a platform toward screening the antioxidant and amyloid inhibitor molecules targeting Cu(II)-induced folding of α-syn in PD.

Electrochemical flow injection analysis of the interaction between pyrroloquinoline quinone (PQQ) and α-synuclein peptides related to Parkinson's disease

α-Synuclein (α-syn) is a hallmark protein of Parkinson's disease (PD). The aggregation process of α-syn has been heavily associated with the pathogenesis of PD. With the exponentially growing number of potential therapeutic compounds that can inhibit the aggregation of α-syn, there is now a significant demand for a high-throughput analysis system. Herein, a novel flow injection analysis system with an electrochemical biosensor as the detector was developed to study the interaction of a well-described antioxidant and amyloid inhibitor, pyrroloquinoline quinone (PQQ) with α-synuclein peptides. Screen-printed gold electrodes (SPEs) were modified using heptapeptides from α-syn wild-type (WT) and mutants such as lysine knock-out (ETEE) and E46K. Affinity binding events between these peptides and PQQ were analyzed by electrochemical impedance spectroscopy (EIS) and further confirmed by high-performance liquid chromatography (HPLC), liquid chromatography/mass spectrometry (LC/MS), and nuclear magnetic resonance (NMR) spectroscopy. HPLC and LC/MS results revealed that PQQ formed a stable complex with α-syn. NMR results confirmed that the α-syn-PQQ complex was formed via a Schiff base formation-like process. In addition, results showed that lysine residues influenced the binding event, in which the presence of an extra lysine stabilized the α-syn-PQQ complex, and the absence of a lysine significantly decreased the interaction of α-syn with PQQ. Therefore, we concluded that EIS is a promising technique for the evaluation of the interaction between PQQ-based amyloid inhibitors and α-syn. The electrochemical flow injection analysis assembly provided a rapid and low-cost drug discovery platform for the evaluation of small molecule-protein interactions.

Structure of a Parkinson's Disease-Involved α-Synuclein Peptide Is Modulated by Membrane Composition and Physical State.

α-Synuclein (AS), the protein responsible for Parkinson's disease, contains a 12-residue-long sequence, AS71-82, that is thought to play a crucial role in the α-synuclein aggregation process. Neuronal membranes are direct interacting partners of α-synuclein and play a role in fibrillogenesis by providing a charged catalytic surface, notably from anionic phospholipids. However, details are lacking regarding the impact of membrane composition and the driving forces leading to membrane anchorage and peptide structure conversion. To decipher the interplay of α-synuclein with neuronal membranes, the structure of AS71-82 was investigated in the presence of anionic model membranes. Infrared (IR) spectroscopy and solid-state nuclear magnetic resonance data show that AS71-82 adopts a perfectly in-register parallel β-sheet structure with fibrillar morphology upon interactions with anionic model membranes. IR thermotropism experiments conducted with several membrane compositions revealed that the phospholipids' phase transition induces a rearrangement of the AS71-82 β-sheet structure. In contrast, membranes are not significantly affected by the presence of AS71-82, which advocates for the amyloid fibrils to lie loosely on the membrane surface. The results bring new arguments for the lipid-sensing capabilities of AS71-82 and revealed its protofibrillar structure. The striking similarities between AS71-82 and α-synuclein make it a potential good aggregation inhibitor upon chemical modifications.

Destabilization and Resisting Growth of Alpha-Synuclein Fibril by Synuclean-D

Parkinson's disease (PD) is a major health condition, but current medications provide only symptomatic relief. The disease is associated with oligomerization of α-synuclein peptides into fibrils in neurons. An effective approach to prevent PD is to use molecular modalities that prevent the growth of nascent fibrils and/or destabilize pre-formed fibrils. Here, we explore the interactions of α-synuclein fibril with SynuClean-D (SCD), a newly discovered drug against PD, by docking, atomistic molecular dynamics (MD) simulations, and enhanced sampling techniques. Our aim is to investigate the mechanism by which SCD might destabilize and/or block the growth of α-synuclein fibrils. Initially, we performed SCD docking to the fibril and found that in the best predicted binding pose, SCD is completely inserted into the fibril core. Furthermore, to investigate the effect of SCD on the fibril, multiple replicas were simulated for 400 ns each in the presence and absence of SCD. The simulations showed that SCD significantly reduces the fibril-backbone H-bonding, thus affecting fibril stability. Next, in order to examine if SCD can enter the core spontaneously, we simulated 10 flooding simulations with 20 randomly distributed copies of SCD surrounding the fibril. In 20% cases, SCD arrived into the core through the end of the fibril and bound to the same domain found by docking. Steered MD simulations and umbrella sampling free energy calculations identified defects in the fibril, caused by loose inter-peptide interactions, through which SCD can enter the interior of the fibril. Moreover, detailed occupancy and clustering analyses of the flooding simulations revealed that SCD made strong interactions with the fibril end, demonstrating its potential to also inhibit fibril growth. These findings are novel in the context of drug-amyloid fibril interactions and offer a platform to design new drug molecules targeting α-synuclein fibrils.

Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro.

Alzheimer’s disease (AD) and Parkinson’s disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of α-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of Aβ(1–42) and pGlu-Aβ(3–42) on the aggregation of α-synuclein in vitro. The aggregation of human recombinant α-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of α-synuclein in the presence of minor concentrations of Aβ(1–42) and pGlu-Aβ(3–42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of α-synuclein and Aβ in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of α-synuclein and Aβ and pGlu-Aβ, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides α-synuclein and Aβ species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases.

Non-steric-zipper models for pathogenic α-synuclein conformers.

Parkinson's disease neurodegenerative brain tissue exhibits two biophysically distinct α-synuclein fiber isoforms—single stranded fibers that appear to be steric-zippers and double-stranded fibers with an undetermined structure. Herein, we describe a β-helical homology model of α-synuclein that exhibits stability in probabilistic and Monte Carlo simulations as a candidate for stable prional dimer conformers in equilibrium with double-stranded fibers and cytotoxic pore assemblies. Molecular models of β-helical pore assemblies are consistent with α-synucleinA53T transfected rat immunofluorescence epitope maps. Atomic force microscopy reveals that α-synuclein peptides aggregate into anisotropic fibrils lacking the density or circumference of a steric-zipper. Moreover, fibrillation was blocked by mutations designed to hinder β-helical but not steric-zipper conformations. β-helical species provide a structural basis for previously described biophysical properties that are incompatible with a steric-zipper, provide pathogenic mechanisms for familial human α-synuclein mutations, and offer a direct cytotoxic target for therapeutic development.

Erratum: T cells from patients with Parkinson's disease recognize α-synuclein peptides.

This corrects the article DOI: 10.1038/nature22815.

Parkinson disease: T cells recognize α-synuclein peptides in Parkinson disease.

Parkinson disease: T cells recognize α-synuclein peptides in Parkinson disease.

T cells from patients with Parkinson's disease recognize α-synuclein peptides.

Genetic studies associate Parkinson’s disease with alleles of the major histocompatibility complex1–3. We find that a defined set of peptides derived from α-synuclein, a protein aggregated in Parkinson’s disease4, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.

Immune response in Parkinson’s disease driven by HLA display of α-synuclein peptides

Abstract Abnormal processing of self-proteins can produce epitopes presented by major histocompatibility (MHC) proteins to be recognized by specific T cells that escaped central tolerance during thymic selection. Such actions by the acquired immune system are widely held to produce autoimmune disorders such as Type-1 diabetes. While not considered to possess autoimmune features, neurodegenerative diseases are characterized by the altered processing of specific proteins. One of the major pathological features of Parkinson’s disease are the presence of intraneuronal aggregrates known as Lewy bodies and neurites composed of α-synuclein. Genetic studies associate Parkinson’s disease with DRB5*01 and DRB1*15:01 MHC alleles. To address the hypothesis that Parkinson’s disease is associated with T cell recognition of epitopes derived from α-synuclein and presented by specific MHC alleles, we recruited 67 Parkinson’s disease patients and 36 age-matched non-Parkinson’s healthy controls. We found that a defined set of peptides derived from α-synuclein, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. We identified two antigenic regions in α-synuclein, the first near the N terminus (aa31-46), which was bound by DRB1*15:01 and DRB5*01:01, and the second near the C terminus, which required phosphorylation of an amino acid residue (S129). These α-synuclein epitopes were shown to arise from natural processing of both extracellular native α-synuclein and the fibrilized form associated with Parkinson’s disease pathogenesis. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.

Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson's disease, a triggering role in the disease?

Environmental factors are implicated in the development of Parkinson's disease (PD). We have investigated on the role of molecular mimicry between HSV1 and α-synuclein that could foster the progression of PD. The antibody response against homologous peptides in PD patients and healthy controls was evaluated, showing that these antibodies are highly prevalent among PD patients to healthy controls. The competitive assay demonstrated cross-reactivity between HSV1 and human α-synuclein peptides. The results may suggest the hypothesis of the involvement of HSV1 in stimulating the immune cells against the neurons of the substantia nigra as a consequence of the cross reactivity.