The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease

14834). Received by CS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Fundacao para a Ciencia e Tecnologia https://www.fct.pt/index.phtml.en (grant number SFRH/BPD/41416/2007; SFRH/BPD/64702/2009; SFRH/BPD/109347/2015; SFRH/BD/61495/2009; Ciencia, 2007; SAU-NEU/105215/2008;). Received by RMO, HVM, PG, TFP, TFO. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dorothea Schlozer Program (University of Gottingen). Received by EMS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JPND: Denmark, Innofond; Germany, BMBF; Sweden, SRC; Switzerland, SNSF; United Kingdom, Medical Research Council www.jpnd.eu. Received by TFO. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Alexander-von-Humboldt Research Fellowship for Postdoctoral Researchers https.//www.humboldt-foundation.de/web/humboldt-fellowship-postdoc.html. Received by LF. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain http://www.cnmpb.de/index.php?lang=en_EN. Received by TFO and MZ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EU Joint Programme - Neurodegenerative Disease Research (JPND) project http://www.neurodegenerationresearch.eu (aSynProtec). Received by TFO. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies. © 2017 de Oliveira et al.publishersversionpublishe