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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00200

Inhibition of nSMase2 reduces the transfer of oligomeric α-synuclein irrespective of hypoxia

  • 1Department of Clinical and Experimental Medicine, Linköping University, Sweden
  • 2Uppsala University, Sweden

Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of α-synuclein (α-syn). However, the regulation of EV biogenesis and its relation to Parkinson’s disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inwards. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of α-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high molecular weight α-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of α-syn. These data show that altering sphingolipids can mitigate the spread of α-syn, even under hypoxic conditions, potentially suppressing PD progression.

Keywords: Parkinson’s disease (PD), Extracellular vesicles (EVs), Neutral sphingomyelinase 2 (nSMase2), α-Syn, hypoxia, cell-to-cell transfer, Sphingomyelin (SM), ceramide

Received: 21 May 2019; Accepted: 02 Aug 2019.

Copyright: © 2019 Sackmann, Sardar Sinha, Sackmann, Civitelli, Bergström, Ansell - Schultz and Hallbeck. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Martin Hallbeck, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Östergötland, Sweden, Martin.Hallbeck@liu.se