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      The neurotransmitter serotonin interrupts α-synuclein amyloid maturation

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          Abstract

          Indolic derivatives can affect fibril growth of amyloid forming proteins. The neurotransmitter serotonin (5-HT) is of particular interest, as it is an endogenous molecule with a possible link to neuropsychiatric symptoms of Parkinson disease. A key pathomolecular mechanism of Parkinson disease is the misfolding and aggregation of the intrinsically unstructured protein α-synuclein. We performed a biophysical study to investigate an influence between these two molecules. In an isolated in vitro system, 5-HT interfered with α-synuclein amyloid fiber maturation, resulting in the formation of partially structured, SDS-resistant intermediate aggregates. The C-terminal region of α-synuclein was essential for this interaction, which was driven mainly by electrostatic forces. 5-HT did not bind directly to monomeric α-synuclein molecules and we propose a model where 5-HT interacts with early intermediates of α-synuclein amyloidogenesis, which disfavors their further conversion into amyloid fibrils.

          Research highlights

          ► The neurotransmitter serotonin (5-HT) suppresses amyloid fibril growth of alpha-synuclein (AS). ► 5-HT binds to intermediate aggregates of alpha-synuclein, not to monomeric AS. Consequently, 5-HT does not influence initial steps of amyloidogenesis. ► 5-HT promotes the accumulation of partially structured, SDS-resistant “on pathway” aggregates of AS. ► The C-terminal region of AS is essential for a charge dependent interaction. ► “On pathway” and “off-pathway” aggregations of AS might mechanistically overlap.

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          Most cited references41

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          Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

          Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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            Stages in the development of Parkinson's disease-related pathology.

            The synucleinopathy, idiopathic Parkinson's disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged. During presymptomatic stages 1-2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3-4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5-6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.
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              alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

              Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.
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                Author and article information

                Journal
                Biochim Biophys Acta
                Biochim. Biophys. Acta
                Biochimica et Biophysica Acta
                Elsevier Pub. Co
                0006-3002
                May 2011
                May 2011
                : 1814
                : 5
                : 553-561
                Affiliations
                [a ]Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
                [b ]Institute of Cell Biology, Histology and Embryology, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria
                [c ]Center for Medical Research, Core Facility Ultrastructure Analysis, Medical University of Graz, 8010 Graz, Austria
                [d ]Institute of Pharmaceutical Sciences, University of Graz, A-8010 Graz, Austria
                [e ]Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
                Author notes
                [* ]Corresponding author. Tel.: +43 316 3805326; fax: +43 316 3809840. fabio.falsone@ 123456uni-graz.at
                Article
                BBAPAP38592
                10.1016/j.bbapap.2011.02.008
                3092864
                21376144
                3ca3cd34-53b2-44c0-8b89-f104e2d78a81
                © 2011 Elsevier B.V.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 21 July 2010
                : 10 February 2011
                : 17 February 2011
                Categories
                Article

                Biochemistry
                5-hiaa, 5-hydroxyindoleacetic acid,protein misfolding,tem, transmission electron spectroscopy,aggregation,5,7-ht, 5,7 dihydroxytryptamine,neurodegeneration,5-ht, serotonin,parkinson disease,indoleamine,dls, dynamic light scattering,nac-region, non-aβ component region,as, α-synuclein,thiot, thioflavin t,amyloid

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