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  Aggregate clearance of α-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome.

Petroi, D., Popova, B., Taheri-Talesh, N., Irniger, S., Shapasandzadeh, H., Zweckstetter, M., et al. (2012). Aggregate clearance of α-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. Journal of Biological Chemistry, 287(33), 27567-27579. doi:10.1074/jbc.M112.361865.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-70AC-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-D0B8-5
Genre: Journal Article

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Petroi, D., Author
Popova, B., Author
Taheri-Talesh, N., Author
Irniger, S., Author
Shapasandzadeh, H., Author
Zweckstetter, M.1, Author              
Outeiro, T. F., Author
Braus, G. H., Author
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1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: Parkinson disease is the second most common neurodegenerative disease. The molecular hallmark is the accumulation of proteinaceous inclusions termed Lewy bodies containing misfolded and aggregated α-synuclein. The molecular mechanism of clearance of α-synuclein aggregates was addressed using the bakers' yeast Saccharomyces cerevisiae as the model. Overexpression of wild type α-synuclein or the genetic variant A53T integrated into one genomic locus resulted in a gene copy-dependent manner in cytoplasmic proteinaceous inclusions reminiscent of the pathogenesis of the disease. In contrast, overexpression of the genetic variant A30P resulted only in transient aggregation, whereas the designer mutant A30P/A36P/A76P neither caused aggregation nor impaired yeast growth. The α-synuclein accumulation can be cleared after promoter shut-off by a combination of autophagy and vacuolar protein degradation. Whereas the proteasomal inhibitor MG-132 did not significantly inhibit aggregate clearance, treatment with phenylmethylsulfonyl fluoride, an inhibitor of vacuolar proteases, resulted in significant reduction in clearance. Consistently, a cim3-1 yeast mutant restricted in the 19 S proteasome regulatory subunit was unaffected in clearance, whereas an Δatg1 yeast mutant deficient in autophagy showed a delayed aggregate clearance response. A cim3-1Δatg1 double mutant was still able to clear aggregates, suggesting additional cellular mechanisms for α-synuclein clearance. Our data provide insight into the mechanisms yeast cells use for clearing different species of α-synuclein and demonstrate a higher contribution of the autophagy/vacuole than the proteasome system. This contributes to the understanding of how cells can cope with toxic and/or aggregated proteins and may ultimately enable the development of novel strategies for therapeutic intervention.

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Language(s): eng - English
 Dates: 2012-06-21
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M112.361865
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 287 (33) Sequence Number: - Start / End Page: 27567 - 27579 Identifier: -