title: Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity.
abstract: Synucleins belong to a family of intrinsically unstructured proteins that includes alpha-synuclein (aSyn), beta-synuclein (bSyn) and gamma-synuclein (gSyn). aSyn is the most studied member of the synuclein family due to its central role in genetic and sporadic forms of Parkinson's disease and other neurodegenerative disorders known as synucleionopathies. In contrast, bSyn and gSyn have been less studied, but recent reports also suggest that, unexpectedly, these proteins may also cause neurotoxicity. Here, we explored the yeast toolbox to investigate the cellular effects of bSyn and gSyn. We found that bSyn is toxic and forms cytosolic inclusions that are similar to those formed by aSyn. Moreover, we found that bSyn shares similar toxicity mechanisms with aSyn, including vesicular trafficking impairment and induction of oxidative stress. We demonstrate that co-expression of aSyn and bSyn exacerbates cytotoxicity, due to increased dosage of toxic synuclein forms, and that they are able to form heterodimers in both yeast and in human cells. In contrast, gSyn is not toxic and does not form inclusions in yeast cells. Altogether, our findings shed light into the question of whether bSyn can exert toxic effects and confirms the occurrence of aSyn/bSyn heterodimers, opening novel perspectives for the development of novel strategies for therapeutic intervention in synucleinopathies.
authors.affiliation: Instituto de Medicina Molecular, Lisboa, Portugal, CEDOC - Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal, stenreiro@nms.unl.pt touteir@gwdg.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Tenreiro
authors.affiliation: Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Rosado-Ramos
authors.affiliation: Department of NeuroDegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Filippo
authors.initials: F
authors.lastname: Favretto
authors.affiliation: Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Magalhães
authors.affiliation: Department of Molecular Microbiology and Genetics, Institute of Microbiology & Genetics, Georg-August-Universität Göttingen, Göttingen, Germany, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Blagovesta
authors.initials: B
authors.lastname: Popova
authors.affiliation: Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany, Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: Department of Molecular Microbiology and Genetics, Institute of Microbiology & Genetics, Georg-August-Universität Göttingen, Göttingen, Germany, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Gerhard H
authors.initials: GH
authors.lastname: Braus
authors.affiliation: CEDOC - Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany, stenreiro@nms.unl.pt touteir@gwdg.de.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D018384:Oxidative Stress; D055503:Protein Multimerization; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D022161:Transport Vesicles; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D051846:beta-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; C497607:SNCB protein, human; D051844:alpha-Synuclein; D051846:beta-Synuclein