Journal ArticleDOI
Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease
Omar M. A. El-Agnaf,Sultan A. Salem,Katerina E. Paleologou,Martin D. Curran,Mark J. Gibson,Jennifer A. Court,Jennifer A. Court,Michael G. Schlossmacher,Michael G. Schlossmacher,David Allsop +9 more
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TLDR
A novel ELISA method is developed that detects only oligomeric “soluble aggregates” of α‐syn in human plasma as a potential biomarker for Parkinson's disease and offers new opportunities for developing diagnostic tests for PD and related diseases.Abstract:
To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). alpha-Synuclein (alpha-syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding alpha-syn in familial cases with early-onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of alpha-syn into insoluble aggregates. We recently reported the presence of alpha-syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether alpha-syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric "soluble aggregates" of alpha-syn. Using this ELISA, we report the presence of significantly elevated (P=0.002) levels of oligomeric forms of alpha-syn in plasma samples obtained from 34 PD patients compared with 27 controls; 52% (95% confidence intervals 0.353-0.687) of the PD patients displayed signals >0.5 OD with our ELISA assay in comparison to only 14.8% (95% confidence intervals 0.014-0.281) for the control cases. An analysis of the test's diagnostic value revealed a specificity of 0.852 (95% confidence intervals 0.662-0.958), sensitivity of 0.529 (95% confidence intervals 0.351-0.702) and a positive predictive value of 0.818 (95% confidence intervals 0.597-0.948). These observations offer new opportunities for developing diagnostic tests for PD and related diseases and for testing therapeutic agents aimed at preventing or reversing the aggregation of alpha-syn.read more
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Journal ArticleDOI
The Parkinson Progression Marker Initiative (PPMI)
Kenneth Marek,Danna Jennings,Shirley Lasch,Andrew Siderowf,Caroline M. Tanner,Tanya Simuni,Christopher S. Coffey,Karl Kieburtz,Emily Flagg,Sohini Chowdhury,Werner Poewe,Brit Mollenhauer,Todd Sherer,Mark Frasier,Claire Meunier,Alice Rudolph,Cindy Casaceli,John Seibyl,Susan Mendick,Norbert Schuff,Ying Zhang,Arthur W. Toga,Karen Crawford,Alison Ansbach,Pasquale De Blasio,Michele Piovella,John Q. Trojanowski,Les Shaw,Andrew B. Singleton,Keith A. Hawkins,Jamie L. Eberling,David W. Russell,Laura Leary,Stewart A. Factor,Barbara Sommerfeld,Penelope Hogarth,Emily Pighetti,Karen Williams,David G. Standaert,Stephanie Guthrie,Robert A. Hauser,Holly Delgado,Joseph Jankovic,Christine Hunter,Matthew B. Stern,Baochan Tran,James B. Leverenz,Marne Baca,Sam Frank,Cathi A. Thomas,Irene H. Richard,Cheryl Deeley,Linda Rees,Fabienne Sprenger,Elisabeth Lang,Holly A. Shill,Sanja Obradov,Hubert H. Fernandez,Adrienna Winters,Daniela Berg,Katharina Gauss,Douglas Galasko,Deborah Fontaine,Zoltan Mari,Melissa Gerstenhaber,David J. Brooks,Sophie Malloy,Paolo Barone,Katia Longo,Tom Comery,Bernard Ravina,Igor D. Grachev,Kim Gallagher,Michelle Collins,Katherine Widnell,Suzanne Ostrowizki,Paulo Fontoura,F. Hoffmann La-Roche,Tony W. Ho,Johan Luthman,Marcel P. van der Brug,Alastair D. Reith,Peggy Taylor +82 more
TL;DR: The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials.
Journal ArticleDOI
Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival.
Evangelia Emmanouilidou,Katerina Melachroinou,Theodoros I. Roumeliotis,Spiros D. Garbis,Maria P. Ntzouni,Lukas H. Margaritis,Leonidas Stefanis,Kostas Vekrellis +7 more
TL;DR: The results show for the first time that cell-produced α- Synuclein is secreted via an exosomal, calcium-dependent mechanism and suggest that α-synuclein secretion serves to amplify and propagate Parkinson's disease-related pathology.
Journal ArticleDOI
α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells
Christian Hansen,Elodie Angot,Ann-Louise Bergström,Jennifer A. Steiner,Laura Pieri,Gesine Paul,Tiago F. Outeiro,Ronald Melki,Pekka Kallunki,Karina Fog,Jia-Yi Li,Patrik Brundin +11 more
TL;DR: In vivo transfer of α-syn between host cells and grafted dopaminergic neurons in mice overexpressing human α- syn and results suggest that α- Syn propagation is a key element in the progression of Parkinson disease pathology.
Journal ArticleDOI
Exosomal cell-to-cell transmission of alpha synuclein oligomers
Karin M Danzer,Karin M Danzer,Lisa R. Kranich,Wolfgang Ruf,Ozge Cagsal-Getkin,Ashley R. Winslow,Liya Zhu,Charles R. Vanderburg,Pamela J. McLean,Pamela J. McLean +9 more
TL;DR: The data suggest that αsyn may be secreted via different secretory pathways, and hypothesize that exosome-mediated release of αsyn oligomers is a mechanism whereby cells clear toxic α synuclein oligomers when autophagic mechanisms fail to be sufficient.
Journal ArticleDOI
Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding
Karin M Danzer,Dorothea Haasen,Anne R. Karow,Simon Moussaud,Matthias Habeck,Armin Giese,Hans A. Kretzschmar,Bastian Hengerer,Marcus Kostka +8 more
TL;DR: The data indicate that inhibition of early α- syn aggregation events would consequently prevent all α-syn oligomer related toxicities, which has important implications for the development of disease-modifying drugs for the treatment of PD and other synucleinopathies.
References
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Journal ArticleDOI
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Journal ArticleDOI
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
Dominic M. Walsh,Igor Klyubin,Julia V. Fadeeva,William K. Cullen,Roger Anwyl,Michael S. Wolfe,Michael J. Rowan,Dennis J. Selkoe +7 more
TL;DR: It is reported that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.
Journal ArticleDOI
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Rakez Kayed,Elizabeth Head,Jennifer L. Thompson,Theresa M. McIntire,Saskia Milton,Carl W. Cotman,Charles G. Glabe +6 more
TL;DR: It is shown that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomer regardless of sequence, suggesting they share a common mechanism of toxicity.
Journal ArticleDOI
α-Synuclein Locus Triplication Causes Parkinson's Disease
Andrew B. Singleton,Matthew J. Farrer,Joshua C. Johnson,Amanda Singleton,Stephen Hague,Jennifer M. Kachergus,Mary M. Hulihan,Terhi Peuralinna,Amalia Dutra,Robert L. Nussbaum,Sarah Lincoln,Anthony Crawley,Melissa Hanson,Demetrius M. Maraganore,Charles H. Adler,Mark R. Cookson,Manfred D. Muenter,Melisa J. Baptista,David Miller,J. Blancato,John Hardy,Katrina Gwinn-Hardy +21 more
TL;DR: In this article, the α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of Parkinson's disease, and of glial cell cytoplasmic inclusions.
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