Silva Guerreiro, Patricia da

[["dc.bibliographiccitation.firstpage","3124"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","3135"],["dc.bibliographiccitation.volume","53"],["dc.contributor.author","Guerreiro, P. S."],["dc.contributor.author","Gerhardt, E."],["dc.contributor.author","Da Fonseca, T. L."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Outeiro, T. F."],["dc.contributor.author","Eckermann, Katrin"],["dc.date.accessioned","2017-09-07T11:44:49Z"],["dc.date.available","2017-09-07T11:44:49Z"],["dc.date.issued","2016"],["dc.description.abstract","Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer's disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD."],["dc.identifier.doi","10.1007/s12035-015-9209-z"],["dc.identifier.gro","3141658"],["dc.identifier.isi","000377935400034"],["dc.identifier.pmid","26014385"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/6231"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1559-1182"],["dc.relation.issn","0893-7648"],["dc.subject","LRRK2; Tau Protein accumulation; Protein degradation"],["dc.title","LRRK2 Promotes Tau Accumulation, Aggregation and Release"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2603"],["dc.bibliographiccitation.issue","19"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.lastpage","2616"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","Pais, Teresa Faria"],["dc.contributor.author","Szego, Eva M."],["dc.contributor.author","Marques, Oldriska"],["dc.contributor.author","Miller-Fleming, Leonor"],["dc.contributor.author","Antas, Pedro"],["dc.contributor.author","Guerreiro, Patricia S."],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Kasapoglu, Burcu"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:18:44Z"],["dc.date.available","2018-11-07T09:18:44Z"],["dc.date.issued","2013"],["dc.description.abstract","Deleterious sustained inflammation mediated by activated microglia is common to most of neurologic disorders. Here, we identified sirtuin 2 (SIRT2), an abundant deacetylase in the brain, as a major inhibitor of microglia-mediated inflammation and neurotoxicity. SIRT2-deficient mice (SIRT2(-/-)) showed morphological changes in microglia and an increase in pro-inflammatory cytokines upon intracortical injection of lipopolysaccharide (LPS). This response was associated with increased nitrotyrosination and neuronal cell death. Interestingly, manipulation of SIRT2 levels in microglia determined the response to Toll-like receptor (TLR) activation. SIRT2 overexpression inhibited microglia activation in a process dependent on serine 331 (S331) phosphorylation. Conversely, reduction of SIRT2 in microglia dramatically increased the expression of inflammatory markers, the production of free radicals, and neurotoxicity. Consistent with increased NF-kappa B-dependent transcription of inflammatory genes, NF-kappa B was found hyperacetylated in the absence of SIRT2, and became hypoacetylated in the presence of S331A mutant SIRT2. This finding indicates that SIRT2 functions as a 'gatekeeper', preventing excessive microglial activation through NF-kappa B deacetylation. Our data uncover a novel role for SIRT2 opening new perspectives for therapeutic intervention in neuroinflammatory disorders."],["dc.identifier.doi","10.1038/emboj.2013.200"],["dc.identifier.isi","000325276800008"],["dc.identifier.pmid","24013120"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/28474"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","0261-4189"],["dc.title","The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","11750"],["dc.bibliographiccitation.issue","34"],["dc.bibliographiccitation.journal","Journal of Neuroscience"],["dc.bibliographiccitation.lastpage","11762"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","Diogenes, Maria Jose"],["dc.contributor.author","Dias, Raquel B."],["dc.contributor.author","Rombo, Diogo M."],["dc.contributor.author","Vicente Miranda, Hugo"],["dc.contributor.author","Maiolino, Francesca"],["dc.contributor.author","Guerreiro, Patricia S."],["dc.contributor.author","Nasstrom, Thomas"],["dc.contributor.author","Franquelim, Henri G."],["dc.contributor.author","Oliveira, Luis M. A."],["dc.contributor.author","Castanho, Miguel A. R. B."],["dc.contributor.author","Lannfelt, Lars"],["dc.contributor.author","Bergstrom, Joakim"],["dc.contributor.author","Ingelsson, Martin"],["dc.contributor.author","Quintas, Alexandre"],["dc.contributor.author","Sebastiao, Ana Maria"],["dc.contributor.author","Lopes, Luisa Vaqueiro"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:07:07Z"],["dc.date.available","2018-11-07T09:07:07Z"],["dc.date.issued","2012"],["dc.description.abstract","Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of alpha-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies."],["dc.identifier.doi","10.1523/JNEUROSCI.0234-12.2012"],["dc.identifier.isi","000308140500021"],["dc.identifier.pmid","22915117"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9413"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/25717"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Soc Neuroscience"],["dc.relation.issn","0270-6474"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","513"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Journal of Molecular Medicine"],["dc.bibliographiccitation.lastpage","522"],["dc.bibliographiccitation.volume","91"],["dc.contributor.author","Guerreiro, Patrícia"],["dc.contributor.author","Huang, Yue"],["dc.contributor.author","Gysbers, Amanda"],["dc.contributor.author","Cheng, Danni"],["dc.contributor.author","Gai, Wei"],["dc.contributor.author","Outeiro, Tiago"],["dc.contributor.author","Halliday, Glenda"],["dc.date.accessioned","2019-07-09T11:39:48Z"],["dc.date.available","2019-07-09T11:39:48Z"],["dc.date.issued","2012"],["dc.description.abstract","Mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are associated with both autosomal dominant and idiopathic forms of Parkinson’s disease (PD). α-Synuclein is the main protein in Lewy bodies, hallmark inclusions present in both sporadic and familial PD. We show that in PD brain tissue, the levels of LRRK2 are positively related to the increase in α-synuclein phosphorylation and aggregation in affected brain regions (amygdala and anterior cingulate cortex), but not in the unaffected visual cortex. In disease-affected regions, we show co-localization of these two proteins in neurons and Lewy body inclusions. Further, in vitro experiments show a molecular interaction between α-synuclein and LRRK2 under endogenous and over-expression conditions. In a cell culture model of α-synuclein inclusion formation, LRRK2 co-localizes with the α-synuclein inclusions, and knocking down LRRK2 increases the number of smaller inclusions. In addition to providing strong evidence for an interaction between LRRK2 and α-synuclein, our results shed light on the complex relationship between these two proteins in the brains of patients with PD and the underlying molecular mechanisms of the disease."],["dc.identifier.doi","10.1007/s00109-012-0984-y"],["dc.identifier.fs","593038"],["dc.identifier.pmid","23183827"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10277"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58037"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Springer"],["dc.publisher.place","Berlin/Heidelberg"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/241791/EU/European Project on Mendelian Forms of Parkinson’s Disease/MEFOPA"],["dc.relation.euproject","MEFOPA"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","LRRK2 interactions with α-synuclein in Parkinson’s disease brains and in cell models"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","113"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","NeuroMolecular Medicine"],["dc.bibliographiccitation.lastpage","121"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Guerreiro, Patricia S."],["dc.contributor.author","Coelho, Joana E."],["dc.contributor.author","Sousa-Lima, Ines"],["dc.contributor.author","Macedo, Paula"],["dc.contributor.author","Lopes, Luisa Vaqueiro"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Pais, Teresa Faria"],["dc.date.accessioned","2018-11-07T10:26:46Z"],["dc.date.available","2018-11-07T10:26:46Z"],["dc.date.issued","2017"],["dc.description.abstract","The protein alpha-synuclein (alpha-Syn) interferes with glucose and lipid uptake and also activates innate immune cells. However, it remains unclear whether alpha-Syn or its familial mutant forms contribute to metabolic alterations and inflammation in synucleinopathies, such as Parkinson's disease (PD). Here, we address this issue in transgenic mice for the mutant A53T human alpha-Syn (alpha-SynA53T), a mouse model of synucleinopathies. At 9.5 months of age, mice overexpressing alpha-SynA53T (homozygous) had a significant reduction in weight, exhibited improved locomotion and did not show major motor deficits compared with control transgenic mice (heterozygous). At 17 months of age, alpha-SynA53T overexpression promoted general reduction in grip strength and deficient hindlimb reflex and resulted in severe disease and mortality in 50 % of the mice. Analysis of serum metabolites further revealed decreased levels of cholesterol, triglycerides and non-esterified fatty acids (NEFA) in alpha-SynA53T-overexpressing mice. In fed conditions, these mice also showed a significant decrease in serum insulin without alterations in blood glucose. In addition, assessment of inflammatory gene expression in the brain showed a significant increase in TNF-alpha mRNA but not of IL-1 beta induced by alpha-SynA53T overexpression. Interestingly, the brain mRNA levels of Sirtuin 2 (Sirt2), a deacetylase involved in both metabolic and inflammatory pathways, were significantly reduced. Our findings highlight the relevance of the mechanisms underlying initial weight loss and hyperactivity as early markers of synucleinopathies. Moreover, we found that changes in blood metabolites and decreased brain Sirt2 gene expression are associated with motor deficits."],["dc.identifier.doi","10.1007/s12017-016-8435-5"],["dc.identifier.isi","000396029500011"],["dc.identifier.pmid","27535567"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43115"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Humana Press Inc"],["dc.relation.issn","1559-1174"],["dc.relation.issn","1535-1084"],["dc.title","Mutant A53T alpha-Synuclein Improves Rotarod Performance Before Motor Deficits and Affects Metabolic Pathways"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1004741"],["dc.bibliographiccitation.journal","PLoS Genetics"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Lazaro, Diana F."],["dc.contributor.author","Rodrigues, Eva F."],["dc.contributor.author","Langohr, Ramona"],["dc.contributor.author","Shahpasandzadeh, Hedieh"],["dc.contributor.author","Ribeiro, Thales"],["dc.contributor.author","Guerreiro, Patricia"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Kroehnert, Katharina"],["dc.contributor.author","Klucken, Jochen"],["dc.contributor.author","Pereira, Marcos D."],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Mollenhauer, Brit"],["dc.contributor.author","Rizzoli, Silvio"],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.author","Danzer, Karin M."],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2017-09-07T11:45:25Z"],["dc.date.available","2017-09-07T11:45:25Z"],["dc.date.issued","2014"],["dc.description.abstract","Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies."],["dc.identifier.doi","10.1371/journal.pgen.1004741"],["dc.identifier.gro","3142024"],["dc.identifier.isi","000345455200011"],["dc.identifier.pmid","25393002"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11136"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3701"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1553-7404"],["dc.relation.issn","1553-7390"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Systematic Comparison of the Effects of Alpha-synuclein Mutations on Its Oligomerization and Aggregation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","149"],["dc.bibliographiccitation.journal","Neurobiology of Disease"],["dc.bibliographiccitation.lastpage","161"],["dc.bibliographiccitation.volume","70"],["dc.contributor.author","Yin, Guowei"],["dc.contributor.author","Da Fonseca, Tomas Lopes"],["dc.contributor.author","Eisbach, Sibylle E."],["dc.contributor.author","Anduaga, Ane Martin"],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Orcellet, Maria L."],["dc.contributor.author","Szego, Eva M."],["dc.contributor.author","Guerreiro, Patricia"],["dc.contributor.author","Lazar, Diana F."],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.author","Fernandez, Claudio O."],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Goody, Roger S."],["dc.contributor.author","Itzen, Aymelt"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2017-09-07T11:45:30Z"],["dc.date.available","2017-09-07T11:45:30Z"],["dc.date.issued","2014"],["dc.description.abstract","Alpha-synuclein (alpha S) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying alpha S toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with alpha S in rodent brain. NMR spectroscopy reveals that the C-terminus of alpha S binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/alpha S interaction, Rab8a enhanced alpha S aggregation and reduced alpha S-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated alpha S-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the alpha S-Rab8a interaction, phosphorylation of alpha S at S129 enhanced binding to Rab8a, increased formation of insoluble alpha S aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and alpha S cytotoxicity, and underscores the therapeutic potential of targeting this interaction. (C) 2014 Elsevier Inc. All rights reserved."],["dc.identifier.doi","10.1016/j.nbd.2014.06.018"],["dc.identifier.gro","3142046"],["dc.identifier.isi","000340691400015"],["dc.identifier.pmid","24983211"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3945"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1095-953X"],["dc.relation.issn","0969-9961"],["dc.title","alpha-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Cellular Neuroscience"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Jacinto, Sandra"],["dc.contributor.author","Guerreiro, Patrícia"],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Cunha-Oliveira, Teresa"],["dc.contributor.author","Santos, Maria João"],["dc.contributor.author","Grazina, Manuela"],["dc.contributor.author","Rego, Ana Cristina"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2021-04-14T08:27:59Z"],["dc.date.available","2021-04-14T08:27:59Z"],["dc.date.issued","2021"],["dc.description.abstract","Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders."],["dc.identifier.doi","10.3389/fncel.2021.641264"],["dc.identifier.pmid","33815063"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/82469"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/304"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1662-5102"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY 4.0"],["dc.title","MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e2000374"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","PLoS Biology"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Miranda, Hugo Vicente"],["dc.contributor.author","Francelle, Laetitia"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Szegoe, Eva Monika"],["dc.contributor.author","Martinho, Renato"],["dc.contributor.author","Munari, Francesca"],["dc.contributor.author","Lazaro, Diana F."],["dc.contributor.author","Moniot, Sebastien"],["dc.contributor.author","Guerreiro, Patricia S."],["dc.contributor.author","Fonseca, Luis"],["dc.contributor.author","Marijanovic, Zrinka"],["dc.contributor.author","Antas, Pedro"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Enguita, Francisco Javier"],["dc.contributor.author","Fauvet, Bruno"],["dc.contributor.author","Penque, Deborah"],["dc.contributor.author","Pais, Teresa Faria"],["dc.contributor.author","Tong, Qiang"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Kuegler, Sebastian"],["dc.contributor.author","Lashuel, Hilal Ahmed"],["dc.contributor.author","Steegborn, Clemens"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:26:48Z"],["dc.date.available","2018-11-07T10:26:48Z"],["dc.date.issued","2017"],["dc.description.abstract","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 ageassociated 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 alpha-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that alpha-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 alpha-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate alpha-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies alpha-synuclein acetylation as a key regulatory mechanism governing alpha-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.1371/journal.pbio.2000374"],["dc.identifier.isi","000397909600002"],["dc.identifier.pmid","28257421"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14377"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43121"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Public Library Science"],["dc.relation.haserratum","/handle/2/102935"],["dc.relation.issn","1545-7885"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e1002601"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLOS Biology"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Vicente Miranda, Hugo"],["dc.contributor.author","Francelle, Laetitia"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Szegö, Éva M."],["dc.contributor.author","Martinho, Renato"],["dc.contributor.author","Munari, Francesca"],["dc.contributor.author","Lázaro, Diana F."],["dc.contributor.author","Moniot, Sébastien"],["dc.contributor.author","Guerreiro, Patrícia"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2022-03-01T11:44:08Z"],["dc.date.available","2022-03-01T11:44:08Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1371/journal.pbio.1002601"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102935"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1545-7885"],["dc.relation.iserratumof","/handle/2/43121"],["dc.rights.uri","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Correction: The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","erratum_ja"],["dspace.entity.type","Publication"]]