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

Oliveira, Rita Machado de; Miranda, Hugo Vicente; Francelle, Laetitia; Pinho, Raquel; Szegő, Éva M.; Martinho, Renato; Munari, Francesca; Lázaro, Diana F.; Moniot, S.; Guerreiro, Patrícia; Fonseca‐Ornelas, Luis; Marijanovic, Zrinka; Antas, Pedro; Gerhardt, Ellen; Enguita, Francisco J.; Fauvet, Bruno; Penque, Deborah; Pais, Teresa F.; Tong, Qiang; Becker, Stefan; Kügler, Sebastian; Lashuel, Hilal A.; Steegborn, Clemens; Zweckstetter, Markus; Outeiro, Tiago F.

doi:10.1371/journal.pbio.2000374

Cited by 135 publications

(145 citation statements)

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“…In addition to N‐terminal acetylation, lysine residues can also undergo acetylation. Mass spectrometry analysis of endogenous AS from mice revealed that Lys6 and Lys10 can be acetylated and that acetylation reduces its aggregation in vitro and reduces toxicity in vivo (de Oliveira et al ).…”

Section: Post‐translational Modifications Of α‐Synucleinmentioning

confidence: 99%

Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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Parkinson’s disease is the second most common neurodegenerative disorder worldwide. Neurodegeneration in this pathology is characterized by the loss of dopaminergic neurons in the substantia nigra, coupled with cytoplasmic inclusions known as Lewy bodies containing α‐synuclein. The brain is an organ that concentrates metal ions, and there is emerging evidence that a break‐down in metal homeostasis may be a critical factor in a variety of neurodegenerative diseases. α‐synuclein has emerged as an important metal‐binding protein in the brain, whereas these interactions play an important role in its aggregation and might represent a link between protein aggregation, oxidative damage, and neuronal cell loss. Additionally, α‐synuclein undergoes several post‐translational modifications that regulate its structure and physiological function, and may be linked to the aggregation and/or oligomer formation. This review is focused on the interaction of this protein with physiologically relevant metal ions, highlighting the cases where metal‐AS interactions profile as key modulators for its structural, aggregation, and membrane‐binding properties. The impact of α‐synuclein phosphorylation and N‐terminal acetylation in the metal‐binding properties of the protein are also discussed, underscoring a potential interplay between PTMs and metal ion binding in regulating α‐synuclein physiological functions and its role in pathology. This article is part of the Special Issue “Synuclein”.

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Section: Post‐translational Modifications Of α‐Synucleinmentioning

confidence: 99%

Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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“…It has been confirmed that selective inhibitors of SIRT2 can protect against α-syn-mediated toxicity and dopaminergic cell death, both in vitro and in a Drosophila model of PD [19]. Notably, a recent study showed that α-syn can be deacetylated by SIRT2, and α-syn acetylation is a key regulatory mechanism governing aggregation and toxicity, demonstrating the potential therapeutic value of SIRT2 inhibition in synucleinopathies [21]. The present study confirmed that mimics of miR-486-3p, which acts as an inhibitor of SIRT2, could reduce the aggregation state of LBs and α-syn-induced neurotoxicity.…”

Section: Discussionmentioning

confidence: 87%

“…A recent study showed that SIRT2 governs α-syn aggregation [21]. To confirm whether miR-486-3p regulates α-syn aggregation through SIRT2, we established a α-syn aggregation model in both SH-SY5Y and U87 cells, involving the co-expression of a C-terminally modified form of α-syn with an increased propensity for aggregation and synphilin-1 (an α-syn interactor that potentiates its aggregation) in neural cells [3].…”

Section: Mir-486-3p Reduces α-Syn Inclusions and Suppresses α-Syn Toxmentioning

confidence: 99%

“…Neurodegeneration induced by a chronic MPTP regimen is prevented by the genetic deletion of SIRT2 in mice [18]. Moreover, the inhibition of SIRT2 in cellular and Drosophila models of PD reduces α-syn-mediated toxicity [19] and also alleviates neuropathology in several models of synucleinopathy by regulating levels of α-syn acetylation, indicating the potential of SIRT2 as a therapeutic intervention for PD by targeting α-syn [20,21].…”

Section: Introductionmentioning

confidence: 99%

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miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

Wang

Cai

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increasing evidence suggests the important role of sirtuin 2 (SIRT2) in the pathology of Parkinson’s disease (PD). However, the association between potential functional polymorphisms in the SIRT2 gene and PD still needs to be identified. Exploring the molecular mechanism underlying this potential association could also provide novel insights into the pathogenesis of this disorder. Methods: Bioinformatics analysis and screening were first performed to find potential microRNAs (miRNAs) that could target the SIRT2 gene, and molecular biology experiments were carried out to further identify the regulation between miRNA and SIRT2 and characterize the pivotal role of miRNA in PD models. Moreover, a clinical case-control study was performed with 304 PD patients and 312 healthy controls from the Chinese Han population to identify the possible association of single nucleotide polymorphisms (SNPs) within the miRNA binding sites of SIRT2 with the risk of PD. Results: Here, we demonstrate that miR-486-3p binds to the 3’ UTR of SIRT2 and influences the translation of SIRT2. MiR-486-3p mimics can decrease the level of SIRT2 and reduce a-synuclein (α-syn)-induced aggregation and toxicity, which may contribute to the progression of PD. Interestingly, we find that a SNP, rs2241703, may disrupt miR-486-3p binding sites in the 3’ UTR of SIRT2, subsequently influencing the translation of SIRT2. Through the clinical case-control study, we further verify that rs2241703 is associated with PD risk in the Chinese Han population. Conclusion: The present study confirms that the rs2241703 polymorphism in the SIRT2 gene is associated with PD in the Chinese Han population, provides the potential mechanism of the susceptibility locus in determining PD risk and reveals a potential target of miRNA for the treatment and prevention of PD.

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“…The explosion in the field of proteostasis in the 2000s, brought about an important knowledge on how cells and organisms handle aSyn, attempting to refold or recycle the protein into its basic components (Cuervo et al ; Bandyopadhyay and Cuervo ). More recently, technological developments in biochemical, biophysical, proteomic, and imaging approaches, provided insight into the structure, chemical modifications (posttranslational modifications, PTMs), and subcellular distribution of aSyn (Mostofi et al ; Goncalves and Outeiro ; de Oliveira et al ; Pinho et al ). Phosphorylation, for example, is widely used as a marker for pathological aSyn (Fujiwara et al ; Paleologou et al ), but other PTMs are emerging as additional studies are performed.…”

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confidence: 99%

Synuclein Meeting 2019: where we are and where we need to go

Outeiro

Mestre

2019

Journal of Neurochemistry

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The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein Meeting is taking place in Ofir, a city in the outskirts of Porto, Portugal. The meeting is entitled ‘Synuclein Meeting 2019: Where we are and where we need to go’. It has now been 22 years since the initial report of the genetic and pathological association between alpha‐synuclein and Parkinson’s disease (PD). The field has grown and matured, and major advances have been made. We are witnessing exciting times, with the first clinical trials being conducted that target synuclein, and bring the hope of novel therapies for patients with PD and their families. However, we still face many challenges and need to address fundamental questions for the field to progress to where we need to go: having biomarkers and effective therapies for PD and other synucleinopathies. In this context, we have designed the Synuclein Meeting 2019 with a different format. The program will include sessions in the format of a round‐table discussion, to break away from the more rigid format of regular scientific meetings based on oral presentations. Our goal was to create opportunities for discussing the major questions in the field of synuclein and related human disorders, and challenge dogmatic ideas that require a critical revision in light of the most recent knowledge. In this issue, we assembled a series of comprehensive overviews of major topics, questions, and challenges in the field, that will be discussed in the meeting. We are confident that this special issue will be an instrumental reference for inspiring novel paths for future discoveries in the synuclein field and generate other discussions in the scientific community. This is the Preface for the Special Issue “Synuclein”. Cover Image for this issue: doi: .

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

Cited by 135 publications

References 48 publications

Effects of alpha‐synuclein post‐translational modifications on metal binding

Effects of alpha‐synuclein post‐translational modifications on metal binding

miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

Synuclein Meeting 2019: where we are and where we need to go

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