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Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© The Author 2015. Published by Oxford University Press.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.

Publication metadata

Author(s): Tenreiro S, Rosado-Ramos R, Gerhardt E, Favretto F, Magalhaes F, Popova B, Becker S, Zweckstetter M, Braus GH, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2016

Volume: 25

Issue: 2

Pages: 275-290

Print publication date: 15/01/2016

Online publication date: 18/11/2015

Acceptance date: 10/11/2015

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddv470

PubMed id: 26586132


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