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      Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission


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          Alpha-synuclein aggregation plays a central role in Parkinson's disease pathology. Direct transmission of alpha-synuclein from pathologically affected to healthy unaffected neurons may be important in the anatomical spread of the disease through the nervous system. We have demonstrated that exosomes released from alpha-synuclein over-expressing SH-SY5Y cells contained alpha-synuclein and these exosomes were capable of efficiently transferring alpha-synuclein protein to normal SH-SY5Y cells. Moreover, the incubation of cells with ammonium chloride or bafilomycin A1 to produce the lysosomal dysfunction recently reported in Parkinson's disease led to an increase in the release of alpha-synuclein in exosomes and a concomitant increase in alpha-synuclein transmission to recipient cells. This study clearly demonstrates the importance of exosomes in both the release of alpha synuclein and its transmission between cells and suggests that factors associated with PD pathology accelerate this process. These mechanisms may play an important role in PD pathology and provide a suitable target for therapeutic intervention.

          Research Highlights

          ► Exosomes released from cells contain α-synuclein. ► Exosomes transfer α-synuclein protein between cells. ► Lysosomal defects seen in Parkinson's disease increase exosomal α-synuclein release. ► Lysosomal dysfunction increases α-synuclein transfer mediate by exosomes.

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          Most cited references24

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          Alpha-synuclein in Lewy bodies.

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            Staging of brain pathology related to sporadic Parkinson's disease.

            Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
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              Proteomic profiling of exosomes: current perspectives.

              Exosomes are 40-100 nm membrane vesicles of endocytic origin secreted by most cell types in vitro. Recent studies have shown that exosomes are also found in vivo in body fluids such as blood, urine, amniotic fluid, malignant ascites, bronchoalveolar lavage fluid, synovial fluid, and breast milk. While the biological function of exosomes is still unclear, they can mediate communication between cells, facilitating processes such as antigen presentation and in trans signaling to neighboring cells. Exosome-like vesicles identified in Drosophila (referred to as argosomes) may be potential vehicles for the spread of morphogens in epithelia. The advent of current MS-based proteomic technologies has contributed significantly to our understanding of the molecular composition of exosomes. In addition to a common set of membrane and cytosolic proteins, it is becoming increasingly apparent that exosomes harbor distinct subsets of proteins that may be linked to cell-type associated functions. The secretion of exosomes by tumor cells and their implication in the transport and propagation of infectious cargo such as prions and retroviruses such as HIV suggest their participation in pathological situations. Interestingly, the recent observation that exosomes contain both mRNA and microRNA, which can be transferred to another cell, and be functional in that new environment, is an exciting new development in the unraveling exosome saga. The present review aims to summarize the physical properties that define exosomes as specific cell-type secreted membrane vesicles.

                Author and article information

                Neurobiol Dis
                Neurobiol. Dis
                Neurobiology of Disease
                Academic Press
                June 2011
                June 2011
                : 42
                : 3
                : 360-367
                [a ]University Department of Clinical Neurosciences, Institute of Neurology, University College London, UK
                [b ]Department of Physiology, Anatomy and Genetics, University of Oxford, UK
                [c ]Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, UK
                Author notes
                [* ]Corresponding author at: Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, UK. Fax: +44 20 7472 6829. l.alvarez@ 123456medsch.ucl.ac.uk
                © 2011 Elsevier Inc.

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

                : 16 September 2010
                : 19 January 2011
                : 28 January 2011

                lysosomal inhibition,bafilomycin a1,transmission,alpha-synuclein,exosome,ammonium chloride


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