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

Tenreiro, S., Rosado-Ramos, R., Gerhardt, E., Favretto, F., Magalhães, F., Popova, B., et al. (2016). Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity. Human Molecular Genetics, 25(2), 275-290. doi:10.1093/hmg/ddv470.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-1C54-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-25E2-1
Genre: Journal Article

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Tenreiro, S., Author
Rosado-Ramos, R., Author
Gerhardt, E., Author
Favretto, F., Author
Magalhães, F., Author
Popova, B., Author
Becker, S.1, Author              
Zweckstetter, M.2, Author              
Braus, G. H., Author
Outeiro, T. F.1, Author              
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 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.

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Language(s): eng - English
 Dates: 2015-11-182016-01-15
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1093/hmg/ddv470
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Title: Human Molecular Genetics
Source Genre: Journal
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Pages: - Volume / Issue: 25 (2) Sequence Number: - Start / End Page: 275 - 290 Identifier: -