Serine 129 phosphorylation of α-synuclein induces unfolded protein response-mediated cell death

Naoto Sugeno, Atsushi Takeda, Takafumi Hasegawa, Michiko Kobayashi, Akio Kikuchi, Fumiaki Mori, Koichi Wakabayashi, Yasuto Itoyama

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81 Citations (Scopus)

Abstract

α-Synuclein is a major protein component deposited in Lewy bodies and Lewy neurites that is extensively phosphorylated at Ser129, although its role in neuronal degeneration is still elusive. In this study, several apoptotic pathways were examined in α-synuclein-overexpressing SH-SY5Y cells. Following the treatment with rotenone, a mitochondrial complex I inhibitor, wild type α-synuclein-overexpressing cells demonstrated intracellular aggregations, which shared a number of features with Lewy bodies, although cells overexpressing the S129A mutant, in which phosphorylation at Ser129 was blocked, showed few aggregations. In wild type α-synuclein cells treated with rotenone, the proportion of phosphorylated α-synuclein was about 1.6 times higher than that of untreated cells. Moreover, induction of unfolded protein response (UPR) markers was evident several hours before the induction of mitochondrial disruption and caspase-3 activation. Eukaryotic initiation factor 2α, a member of the PERK pathway family, was remarkably activated at early phases. On the other hand, the S129A mutant failed to activate UPR. Casein kinase 2 inhibitor, which decreased α-synuclein phosphorylation, also reduced UPR activation. The α-synuclein aggregations were colocalized with a marker for the endoplasmic reticulum-Golgi intermediate compartment. Taken together, it seems plausible that α-synuclein toxicity is dependent on the phosphorylation at Ser129 that induces the UPRs, possibly triggered by the disturbed endoplasmic reticulum-Golgi trafficking.

Original languageEnglish
Pages (from-to)23179-23188
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number34
DOIs
Publication statusPublished - 2008 Aug 22

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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