Alpha-Synuclein and 14-3-3 Proteins as Biomarkers of Neurodegenerative Diseases

2014 ◽  
pp. 506-531
Keyword(s):  
Neurodegenerative Diseases ◽  
Alpha Synuclein

scholarly journals Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Martin Nors Pedersen ◽  
Vito Foderà ◽  
Istvan Horvath ◽  
Andreas van Maarschalkerweerd ◽  
Katrine Nørgaard Toft ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Angle ◽  
Alpha Synuclein ◽  
X Ray ◽  
Transient Nature ◽  
X Ray Scattering ◽  
Amyloid Deposits ◽  
Potential Link ◽  
Presence And Absence

Abstract Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075) and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an ‘oligomer stacking model’ for alpha-synuclein fibril elongation.

scholarly journals Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Nelson de Oliveira Manzanza ◽  
Lucia Sedlackova ◽  
Raj N. Kalaria
Keyword(s):  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Clinical Symptoms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Post Translational Modifications ◽  
Age Related ◽  
Neurodegenerative Dementias

Lewy Body Disorders (LBDs) lie within the spectrum of age-related neurodegenerative diseases now frequently categorized as the synucleinopathies. LBDs are considered to be among the second most common form of neurodegenerative dementias after Alzheimer's disease. They are progressive conditions with variable clinical symptoms embodied within specific cognitive and behavioral disorders. There are currently no effective treatments for LBDs. LBDs are histopathologically characterized by the presence of abnormal neuronal inclusions commonly known as Lewy Bodies (LBs) and extracellular Lewy Neurites (LNs). The inclusions predominantly comprise aggregates of alpha-synuclein (aSyn). It has been proposed that post-translational modifications (PTMs) such as aSyn phosphorylation, ubiquitination SUMOylation, Nitration, o-GlcNacylation, and Truncation play important roles in the formation of toxic forms of the protein, which consequently facilitates the formation of these inclusions. This review focuses on the role of different PTMs in aSyn in the pathogenesis of LBDs. We highlight how these PTMs interact with aSyn to promote misfolding and aggregation and interplay with cell membranes leading to the potential functional and pathogenic consequences detected so far, and their involvement in the development of LBDs.

scholarly journals Cryo-EM structure of alpha-synuclein fibrils amplified by PMCA from PD and MSA patient brains

2021 ◽  
Author(s):  
Domenic Burger ◽  
Alexis Fenyi ◽  
Luc Bousset ◽  
Henning Stahlberg ◽  
Ronald Melki
Keyword(s):  
Multiple System Atrophy ◽  
Parkinson Disease ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Brain Homogenate ◽  
Alpha Synuclein ◽  
Water Interface ◽  
Control Brain ◽  
Air Water Interface

Synucleinopathies are neurodegenerative diseases related to the aggregation of the protein alpha-synuclein (aSyn). Among these diseases, Parkinson disease (PD) and multiple system atrophy (MSA) are most prevalent. aSyn can readily form different fibrillar polymorphs, if exposed to an air-water interface or by templating with pre-existing fibrils. We here report the structures of three fibrillar polymorphs that were obtained after seeding monomeric aSyn with PD and MSA patients brain homogenates using protein misfolding cyclic amplification (PMCA). Seeding with a control brain homogenate did not produce fibrils, and seeding with other in vitro generated fibrillar polymorphs as a control faithfully produced polymorphs of a different type. The here determined fibril structures from PD and MSA brain tissue represent new folds, which partly resemble that of previously reported in vitro generated fibrils from Y39 phosphorylated aSyn protein. The relevance of these fibrils for synucleinopathies in humans remains to be further investigated.

scholarly journals Rab2 is a potent new target for enhancing autophagy in the treatment of Parkinson’s disease

2020 ◽  
Author(s):  
Janka Szinyákovics ◽  
Eszter Kiss ◽  
Fanni Keresztes ◽  
Tibor Vellai ◽  
Tibor Kovács
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Drug Targets ◽  
Disease Model ◽  
Alpha Synuclein ◽  
Small Gtpase ◽  
Rab Proteins ◽  
Receptor Complexes ◽  
Complex Forms

AbstractMacroautophagy is a lysosomal-dependent degradational pathway of eukaryotic cells, during which toxic, unnecessary, and damaged intracellular components are broken down. Autophagic activity declines with age, and this change could contribute to the accumulation of intracellular damage at advanced ages, causing cells to lose their functionality and vitality. This could be particularly problematic in post-mitotic cells include neurons, the mass destruction of which leads to different neurodegenerative diseases.We aim to discover new regulation points where autophagy could be specifically activated, and test these potential drug targets in Drosophila neurodegenerative disease models. One possible way to activate autophagy is through the enhancement of autophagosome-lysosome fusion to become autolysosome. This fusion is regulated by HOPS (homotypic fusion and protein sorting) and SNARE (Snap receptor) complexes. The HOPS complex forms a bridge between lysosome and autophagosome with the assistance of small GTPase Rab (Ras-associated binding) proteins. Thus, Rab proteins are essential for autolysosome maturation, and among Rab proteins, Rab2 is required for the degradation of autophagic cargo.Our results revealed that GTP-locked (constitutively active) Rab2 (Rab2 CA) expression reduces the levels of the autophagic substrate p62/Ref2P in dopaminergic neurons, and improved the climbing ability of animals during aging. The expression of Rab2 CA also increased lifespan in a Parkinson’s disease model (human mutant alpha-synuclein [A53T] overexpressed animals). In these animals, Rab2 CA expression significantly increased autophagic degradation as compared to control. These results may reveal a new, more specific drug target for autophagic activation treating today’s incurable neurodegenerative diseases.

Targeted Downregulation of Estradiol Binding Na+/H+ Exchanger Nhx-2, Mimics Calorie Restriction, Extends Reproductive Longevity and Ameliorates Effects Associated With Alpha Synuclein Aggregation In C. Elegans

2021 ◽  
Author(s):  
Shikha Shukla ◽  
Lalit Kumar ◽  
Arunabh Sarkar ◽  
Kottapalli Srivi ◽  
Aamir Nazir
Keyword(s):  
Reproductive Health ◽  
Neurodegenerative Diseases ◽  
Functional Characterization ◽  
Alpha Synuclein ◽  
Binding Potential ◽  
Estradiol Treatment ◽  
Reproductive Senescence ◽  
Knock Out ◽  
C Elegans ◽  
Alpha Synuclein Aggregation

Abstract Setting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to multiple disorders including neurodegenerative diseases, cardiovascular ailments and bone disorders amongst others. The present study, employing transgenic C. elegans that expresses ‘human’ alpha synuclein, endeavors to decipher the association of reproductive senescence with age-associated neurodegenerative diseases and behavioral ageing, under normal conditions and after being probed with estradiol. We carried out RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects. These studies led us to functional characterization of the Na+/H+ exchanger; nhx-2, expressed exclusively in gut. We found that RNAi of nhx-2 not only ameliorates the effects associated with alpha-Synuclein aggregation, but it also attunes effects related to behavioral aging including that of reproductive health-span and neuroprotection via mimicking dietary restriction, as it alters food absorption from the gut. We further elucidated that these effects are Sir-2.1 driven as nhx-2 knock out did not delay reproductive senescence in knock down condition of sir-2.1. To substantiate our findings, we performed whole transcriptome analysis in nhx-2 mutant strain. Our data revealed differential expression of 61 out of 62 hallmark genes of CR described by GenDR, in knock out condition of nhx-2. As estradiol plays a central role in both reproductive health as well as neuronal health, we subjected worms to exogenous estradiol treatment and observed that it led to elevated levels of nhx-2. Studies on structural binding analysis demonstrated significant binding potential of estradiol receptor NHR-14 with nhx-2 gene and ChIP analysis revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3). These studies identify nhx-2 as an important modulator that extends reproductive longevity and ameliorates effects associated with alpha synuclein aggregation in C elegans.

scholarly journals Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson’s Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8666
Author(s):  
Dominika Fricova ◽  
Jana Harsanyiova ◽  
Alzbeta Kralova Trancikova
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Clinical Symptoms ◽  
Neuronal Degeneration ◽  
Alpha Synuclein ◽  
Diagnostic Methods ◽  
Alternative Methods ◽  
Peripheral Tissues ◽  
Potential Biomarker

The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.

P4-195: Mitochondrial alpha-synuclein: Implications in neurodegenerative diseases

2009 ◽  
Vol 5 (4S_Part_16) ◽  
pp. P488-P488
Author(s):  
Kenji Uéda ◽  
Guangwei Liu ◽  
Chunyan Zhang ◽  
Juanjuan Yin ◽  
Xin Li ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Alpha Synuclein
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