scholarly journals Unravelling the effect of N(ε)-(carboxyethyl)lysine on the conformation, dynamics and aggregation propensity of α-synuclein

2020 ◽  
Vol 11 (12) ◽  
pp. 3332-3344 ◽  
Author(s):  
Laura Mariño ◽  
Rafael Ramis ◽  
Rodrigo Casasnovas ◽  
Joaquín Ortega-Castro ◽  
Bartolomé Vilanova ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Advanced Glycation ◽  
Advanced Glycation End Product ◽  
Aggregation Propensity

We study the effect of an advanced glycation end product (N(ε)-(carboxyethyl)lysine), found on the Lewy bodies of people suffering from Parkinson’s disease, on the conformational and aggregation features of alpha-synuclein.

scholarly journals Microbiome, Parkinson’s Disease and Molecular Mimicry

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 222 ◽  
Author(s):  
Fabiana Miraglia ◽  
Emanuela Colla
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mimicry ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Causative Role ◽  
Olfactory Bulbs ◽  
Host Interactions ◽  
Aggregation Propensity

Parkinson’s Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD. In this article, we will be reviewing current knowledge on the importance of the microbiota in PD pathology, concentrating our investigation on mechanisms of microbiota-host interactions that might become harmful and favor the onset of PD. Such processes, which include the secretion of bacterial amyloid proteins or other metabolites, may influence the aggregation propensity of αS directly or indirectly, for example by favoring a pro-inflammatory environment in the gut. Thus, while the development of PD has not yet being associated with a unique microbial species, more data will be necessary to examine potential harmful interactions between the microbiota and the host, and to understand their relevance in PD pathogenesis.

scholarly journals Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

2018 ◽  
Author(s):  
Tim E. Moors ◽  
Christina A. Maat ◽  
Daniel Niedieker ◽  
Daniel Mona ◽  
Dennis Petersen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Distribution Patterns ◽  
Alpha Synuclein ◽  
Label Free ◽  
Post Translational Modifications ◽  
Sted Microscopy ◽  
C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

scholarly journals Cryo-EM structure of alpha-synuclein fibrils

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ricardo Guerrero-Ferreira ◽  
Nicholas MI Taylor ◽  
Daniel Mona ◽  
Philippe Ringler ◽  
Matthias E Lauer ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Diagnosis And Treatment ◽  
Lewy Neurites ◽  
Cryo Electron Microscopy ◽  
High Concentrations ◽  
Hydrophobic Cleft

Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1–121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50–57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

What Is Known about the Cause

2013 ◽  
Author(s):  
J. Eric Ahlskog
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Medical Center ◽  
Single Gene ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Early Years ◽  
Gene Coding ◽  
Sporadic Parkinson’S Disease ◽  
High Concentrations

Most of the research into the cause of Lewy disorders has focused on Parkinson’s disease, since that is the best defined of these conditions and, therefore, the most straightforward to study. Dementia with Lewy bodies (DLB) is more difficult to diagnose with certainty, especially in the early years of the disease. What we collectively learn about Parkinson’s disease will likely be very relevant to our understanding of DLB. Multiple investigations have linked Parkinson’s disease to both environmental exposures and genetic factors. However, these associations have all been modest, and none of them accounts for more than a few percent of the contribution to the cause of sporadic Parkinson’s disease (i.e., the attributable risks are low). These investigations are ongoing and hopefully will soon provide a more complete understanding of the cause(s). Perhaps the most important clue to all Lewy conditions is located in the brain: the Lewy body itself. A recent sophisticated analysis of Lewy bodies revealed approximately 300 different component proteins. However, we already knew that Lewy bodies contain high concentrations of a normal protein called alpha synuclein. In fact, Lewy bodies are conventionally identified under the microscope with antibody stains that specifically bind to alpha synuclein. Could this be the crucial protein among the nearly 300? While the alpha synuclein story is focused on Parkinson’s disease, it may be just as relevant to DLB, as we shall see. The story starts with a large Italian-American family with Parkinson’s disease, studied by Dr. Lawrence Golbe and colleagues at the Robert Wood Johnson Medical Center in New Brunswick, New Jersey. In this rare family, many members of multiple generations had been affected by Parkinson’s disease (with Lewy bodies), consistent with a single gene passed on with dominant inheritance. It took a number of years to identify that abnormal gene, which ultimately was proven to be the gene coding for alpha synuclein. It was quickly discovered that this genetic error is not present in usual cases of Parkinson’s disease.

scholarly journals Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2289 ◽  
Author(s):  
Sanjanie Fernando ◽  
Claire Y. Allan ◽  
Katelyn Mroczek ◽  
Xavier Pearce ◽  
Oana Sanislav ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dictyostelium Discoideum ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Cell Cortex ◽  
Mutant Proteins ◽  
C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

scholarly journals Blood Plasma of Patients with Parkinson’s Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Peng Wang ◽  
Xin Li ◽  
Xuran Li ◽  
Weiwei Yang ◽  
Shun Yu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alternative Pathway ◽  
Lewy Bodies ◽  
Normal Subjects ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Alpha Synuclein Aggregation ◽  
The Brain ◽  
Neighboring Neuron

A pathological hallmark of Parkinson’s disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn. This was supported by the observations that phosphorylated α-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote α-syn phosphorylation and aggregation. We also analyzed neurotoxicity of α-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of α-syn aggregates via an alternative pathway and accelerate progression of PD.

scholarly journals Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1333
Author(s):  
Maxime Teixeira ◽  
Razan Sheta ◽  
Walid Idi ◽  
Abid Oueslati
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Cellular Membrane ◽  
Degradation Pathway ◽  
Alpha Synuclein ◽  
Potential Interaction ◽  
Abnormal Accumulation ◽  
Cellular Components

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.

scholarly journals Combined Analysis of CSF Tau, Aβ42, Aβ1–42% and Aβ1–40ox% in Alzheimer's Disease, Dementia with Lewy Bodies and Parkinson's Disease Dementia

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Mirko Bibl ◽  
Hermann Esselmann ◽  
Piotr Lewczuk ◽  
Claudia Trenkwalder ◽  
Markus Otto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Diagnostic Value ◽  
Alpha Synuclein ◽  
Parkinson’S Disease Dementia ◽  
Sds Page

We studied the diagnostic value of CSF Aβ42/tau versus low Aβ1–42% and high Aβ1–40ox% levels for differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), respectively. CSF of 45 patients with AD, 15 with DLB, 21 with Parkinson's disease dementia (PDD), and 40 nondemented disease controls (NDC) was analyzed by Aβ-SDS-PAGE/immunoblot and ELISAs (Aβ42 and tau). Aβ42/tau lacked specificity in discriminating AD from DLB and PDD. Best discriminating biomarkers were Aβ1–42% and Aβ1–40ox% for AD and DLB, respectively. AD and DLB could be differentiated by both Aβ1–42% and Aβ1–40ox% with an accuracy of 80% at minimum. Thus, we consider Aβ1–42% and Aβ1–40ox% to be useful biomarkers for AD and DLB, respectively. We propose further studies on the integration of Aβ1–42% and Aβ1–40ox% into conventional assay formats. Moreover, future studies should investigate the combination of Aβ1–40ox% and CSF alpha-synuclein for the diagnosis of DLB.

scholarly journals Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

2020 ◽  
pp. 1-22
Author(s):  
Anne-Marie Castonguay ◽  
Claude Gravel ◽  
Martin Lévesque
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Passive Immunization ◽  
Lewy Bodies ◽  
Gene Mutations ◽  
Alpha Synuclein ◽  
Multiple Sources ◽  
Immunization Strategies ◽  
A Cell

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

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