Outeiro, Tiago Fleming

[["dc.bibliographiccitation.firstpage","120"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Brain Pathology"],["dc.bibliographiccitation.lastpage","132"],["dc.bibliographiccitation.volume","31"],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Bondarevaite, Odeta"],["dc.contributor.author","Adams, Sara"],["dc.contributor.author","Leite, Marta"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Attems, Johannes"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2021-04-14T08:24:10Z"],["dc.date.available","2021-04-14T08:24:10Z"],["dc.date.issued","2020"],["dc.description.abstract","Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X-linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha-Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post-mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co-localized with beta-amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B-associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co-aggregation of RAB39B with Aβ in plaques suggests that age-associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases."],["dc.identifier.doi","10.1111/bpa.12890"],["dc.identifier.pmid","32762091"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81186"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/166"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/97"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration"],["dc.relation.eissn","1750-3639"],["dc.relation.issn","1015-6305"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY 4.0"],["dc.title","RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Movement Disorders"],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Campesan, Susanna"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2021-06-01T09:42:12Z"],["dc.date.available","2021-06-01T09:42:12Z"],["dc.date.issued","2021"],["dc.description.abstract","Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society"],["dc.identifier.doi","10.1002/mds.28605"],["dc.identifier.pmid","33939203"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85175"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/271"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/124"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration"],["dc.relation.eissn","1531-8257"],["dc.relation.issn","0885-3185"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY 4.0"],["dc.title","Dysfunction of RAB39B‐ Mediated Vesicular Trafficking in Lewy Body Diseases"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","overview_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","65.e6"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell Reports"],["dc.bibliographiccitation.lastpage","77.e6"],["dc.bibliographiccitation.volume","28"],["dc.contributor.author","Szegő, Éva M."],["dc.contributor.author","Dominguez-Meijide, Antonio"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","König, Annekatrin"],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Li, Wen"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Fahlbusch, Christiane"],["dc.contributor.author","Johnson, Mary"],["dc.contributor.author","Santos, Patricia"],["dc.contributor.author","Villar-Piqué, Anna"],["dc.contributor.author","Thom, Tobias"],["dc.contributor.author","Rizzoli, Silvio"],["dc.contributor.author","Schmitz, Matthias"],["dc.contributor.author","Li, Jiayi"],["dc.contributor.author","Zerr, Inga"],["dc.contributor.author","Attems, Johannes"],["dc.contributor.author","Jahn, Olaf"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2021-04-26T14:09:42Z"],["dc.date.available","2021-04-26T14:09:42Z"],["dc.date.issued","2019"],["dc.description.abstract","Alpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice. The levels of superoxide dismutase 2, a client of the HSP10/HSP60 folding complex, and synaptosomal spare respiratory capacity are also reduced. Overexpression of HSP10 ameliorates aSyn-associated mitochondrial dysfunction and delays aSyn pathology in vitro and in vivo. Altogether, our data indicate that increased levels of aSyn induce mitochondrial deficits, at least partially, by sequestering HSP10 in the cytosol and preventing it from acting in mitochondria. Importantly, these alterations manifest first at presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies but opens new avenues for targeting underlying cellular pathologies."],["dc.identifier.doi","10.1016/j.celrep.2019.06.009"],["dc.identifier.pmid","31269451"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16257"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/84389"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/6"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration"],["dc.relation.eissn","2211-1247"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.relation.workinggroup","RG Rizzoli (Quantitative Synaptology in Space and Time)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dc.type.version","submitted_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Brain: A Journal of Neurology"],["dc.contributor.author","Hatton, Christopher"],["dc.contributor.author","Ghanem, Simona S."],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Abdi, Ilham Y."],["dc.contributor.author","Gibbons, Elizabeth"],["dc.contributor.author","Guerreiro, Rita"],["dc.contributor.author","Bras, Jose"],["dc.contributor.author","Walker, Lauren"],["dc.contributor.author","Gelpi, Ellen"],["dc.contributor.author","Heywood, Wendy"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Attems, Johannes"],["dc.contributor.author","McFarland, Robert"],["dc.contributor.author","Forsyth, Rob"],["dc.contributor.author","El-Agnaf, Omar M."],["dc.contributor.author","Erskine, Daniel"],["dc.date.accessioned","2022-02-22T15:58:07Z"],["dc.date.available","2022-02-22T15:58:07Z"],["dc.date.issued","2022-01-06"],["dc.description.abstract","Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (N = 4) compared to infant controls (N = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease."],["dc.identifier.doi","10.1093/brain/awac002"],["dc.identifier.pmid","34999780"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100198"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/388"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/148"],["dc.language.iso","en"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation.eissn","1460-2156"],["dc.relation.issn","0006-8950"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY-NC 4.0"],["dc.title","Prion-like α-synuclein pathology in the brain of infants with Krabbe disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","unpublished"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","5"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Molecular Neurodegeneration"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Erskine, Daniel"],["dc.contributor.author","Walker, Lauren"],["dc.contributor.author","Kurzawa-Akanbi, Marzena"],["dc.contributor.author","Burn, David"],["dc.contributor.author","Donaghy, Paul"],["dc.contributor.author","Morris, Christopher"],["dc.contributor.author","Taylor, John-Paul"],["dc.contributor.author","Thomas, Alan"],["dc.contributor.author","Attems, Johannes"],["dc.contributor.author","McKeith, Ian"],["dc.date.accessioned","2019-07-09T11:51:10Z"],["dc.date.available","2019-07-09T11:51:10Z"],["dc.date.issued","2019"],["dc.description.abstract","Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies."],["dc.identifier.doi","10.1186/s13024-019-0306-8"],["dc.identifier.pmid","30665447"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16061"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59887"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","006"],["dc.subject.ddc","573"],["dc.subject.ddc","612"],["dc.title","Dementia with Lewy bodies: an update and outlook"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]