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Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells
Uppsala Univ, Sweden.
Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
Uppsala Univ, Sweden.
Univ Med Ctr Gottingen, Germany.
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2018 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed) Published
Abstract [en]

In Parkinsons disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular -synuclein (-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of -syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of -syn can influence the distribution and secretion of -syn in human neuroblastoma cells. Different -syn variants, including -syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted -syn, 0.1-2% was associated with vesicles. The major part of EV -syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For -syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT -syn. Moreover, such EV-associated -syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T -syn displayed an increased association with EVs. Taken together, our data suggest that -syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful -syn species and thereby contribute to the pathology in -synucleinopathies.

Place, publisher, year, edition, pages
SPRINGER/PLENUM PUBLISHERS , 2018. Vol. 38, no 8, p. 1539-1550
Keywords [en]
Alpha-synuclein; Parkinsons disease; Alpha-synuclein oligomers; Human neuroblastoma; Extracellular vesicles; Exosomes
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-152810DOI: 10.1007/s10571-018-0622-5ISI: 000449258300008PubMedID: 30288631OAI: oai:DiVA.org:liu-152810DiVA, id: diva2:1265288
Note

Funding Agencies|U4 Ageing Brain Network; Swedish Research Council [2011-4519, 2012-2172, 2010-6745, 2013-2735]; Marianne and Marcus Wallenberg Foundation; Swedish Brain Foundation; Parkinson Research Foundation; Swedish Alzheimer Foundation; Swedish Parkinson Foundation; Swedish Society of Medicine; Hans-Gabriel and Alice Trolle Wachtmeisters Foundation for Medical Research; Lundbeck Foundation; Stohnes Foundation; Soderstrom-Konigska Foundation; Swedish Dementia Foundation; Bjorklunds Foundation for ALS research; Magnus Bergwall Foundation; Thore Nilsson Foundation; Old Servants Foundation; Ahlen Foundation; Loo and Hans Ostermans Foundation; Jeanssons Foundation; Larsson-Rosts Foundation; King Gustaf Vs and Queen Victorias Freemason Foundation; Goransson Sandvikens Foundation; NIH [NCI U19 CA179563]; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB); Uppsala Berzelii Technology Center for Neurodiagnostics; Anna Maria Lundin Foundation; Goljes Foundation

Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-10-14

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