On the mechanism of internalization of α-synuclein into microglia: Roles of ganglioside GM1 and lipid raft

Ji Young Park, Kwang Soo Kim, Saet Byul Lee, Jae Sung Ryu, Kwang Chul Chung, Young Kug Choo, Ilo Jou, Jongsun Kim, Sang Myun Park

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Abstract

α-Synuclein (α-syn) has been known to be a key player of the pathogenesis of Parkinson's disease and has recently been detected in extracellular biological fluids and shown to be rapidly secreted from cells. The penetration of α-syn into cells has also been observed. In this study, we observed that dl-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glucosyltransferase inhibitor, and proteinase K inhibited the internalization of extracellular monomeric α-syn into BV-2 cells, and the addition of monosialoganglioside GM1 ameliorated the inhibition of α-syn internalization in dl-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol- treated BV-2 cells. Furthermore, inhibition of clathrin-, caveolae-, and dynamin-dependent endocytosis did not prevent the internalization of α-syn, but disruption of lipid raft inhibited it. Inhibition of macropinocytosis and disruption of actin and microtubule structures also did not inhibit the internalization of α-syn. In addition, we further confirmed these observations by co-culture system of BV-2 cells and α-syn-over- expressing SH-SY5Y cells. These findings suggest that extracellular α-syn is internalized into microglia via GM1 as well as hitherto-unknown protein receptors in clathrin-, caveolae-, and dynamin-independent, but lipid raft-dependent manner. Elucidation of the mechanism involved in internalization of α-syn should be greatly helpful in the development of new treatments of α-syn-related neurodegenerative diseases.

Original languageEnglish
Pages (from-to)400-411
Number of pages12
JournalJournal of Neurochemistry
Volume110
Issue number1
DOIs
Publication statusPublished - 2009 Jul 1

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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