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Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/6206

Título: Synphilin-1 enhances α-synuclein aggregation in yeast and contributes to cellular stress and cell death in a Sir2-dependent manner
Autor: Büttne, Sabrina
Delay, Charlotte
Franssens, Vanessa
Bammens, Tine
Ruli, Doris
Zaunschirm, Sandra
Oliveira, Rita Machado de
Outeiro, Tiago Fleming
Madeo, Frank
Buée, Luc
Galas, Marie-Christine
Winderickx, Joris
Palavras-chave: Alpha-synuclein
Cell aggregation
Cell death
Parkinson disease
Issue Date: 2010
Editora: Public Library of Science
Citação: PLoS ONE 5(10): e13700
Resumo: Background: Parkinson’s disease is characterized by the presence of cytoplasmic inclusions, known as Lewy bodies, containing both aggregated α-synuclein and its interaction partner, synphilin-1. While synphilin-1 is known to accelerate inclusion formation by α-synuclein in mammalian cells, its effect on cytotoxicity remains elusive. Methodology/Principal Findings: We expressed wild-type synphilin-1 or its R621C mutant either alone or in combination with α-synuclein in the yeast Saccharomyces cerevisiae and monitored the intracellular localization and inclusion formation of the proteins as well as the repercussions on growth, oxidative stress and cell death. We found that wild-type and mutant synphilin-1 formed inclusions and accelerated inclusion formation by α-synuclein in yeast cells, the latter being correlated to enhanced phosphorylation of serine-129. Synphilin-1 inclusions co-localized with lipid droplets and endomembranes. Consistently, we found that wild-type and mutant synphilin-1 interacts with detergent-resistant membrane domains, known as lipid rafts. The expression of synphilin-1 did not incite a marked growth defect in exponential cultures, which is likely due to the formation of aggresomes and the retrograde transport of inclusions from the daughter cells back to the mother cells. However, when the cultures approached stationary phase and during subsequent ageing of the yeast cells, both wild-type and mutant synphilin-1 reduced survival and triggered apoptotic and necrotic cell death, albeit to a different extent. Most interestingly, synphilin-1 did not trigger cytotoxicity in ageing cells lacking the sirtuin Sir2. This indicates that the expression of synphilin-1 in wild-type cells causes the deregulation of Sir2-dependent processes, such as the maintenance of the autophagic flux in response to nutrient starvation. Conclusions/Significance: Our findings demonstrate that wild-type and mutant synphilin-1 are lipid raft interacting proteins that form inclusions and accelerate inclusion formation of α-synuclein when expressed in yeast. Synphilin-1 thereby induces cytotoxicity, an effect most pronounced for the wild-type protein and mediated via Sir2-dependent processes.
Descrição: © 2010 Büttner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Arbitragem científica: yes
URI: http://hdl.handle.net/10451/6206
ISSN: 1932-6203
Appears in Collections:IMM - Artigos em Revistas Internacionais

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