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Bouman, L.* ; Schlierf, A.* ; Lutz, A.K.* ; Shan, J.* ; Deinlein, A.* ; Kast, J.* ; Galehdar, Z.* ; Palmisano, V.* ; Patenge, N.* ; Berg, D.* ; Gasser, T.* ; Augustin, R. ; Trümbach, D. ; Irrcher, I.* ; Park, D.S.* ; Wurst, W. ; Kilberg, M.S.* ; Tatzelt, J.* ; Winklhofer, K.F.*

Parkin is transcriptionally regulated by ATF4: Evidence for an interconnection between mitochondrial stress and ER stress.

Cell Death Differ. 18, 769-782 (2011)
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Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter ATF4; c-Jun; ER stress; parkin; Parkinson's disease; UPR
Sprache englisch
Veröffentlichungsjahr 2011
Prepublished im Jahr 2010
HGF-Berichtsjahr 2010
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Zeitschrift Cell Death and Differentiation
Quellenangaben Band: 18, Heft: 5, Seiten: 769-782 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500500-001
G-500500-003
PubMed ID 21113145
DOI 10.1038/cdd.2010.142
Erfassungsdatum 2010-12-23
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