LETTER

Role of the hsp70 cochaperone BAG1 in glucocorticoid receptor function and stress-related diseases The article by Maeng et al. (1) reports on the role of the hsp70 cochaperone BAG1 in manic-like and depression-like behavioral phenotypes in mice. The authors discuss their results in connection with the established role of BAG1 in regulating the function of the glucocorticoid receptor (GR). They highlight this role of BAG1 because mania and depression are widely considered to be stress-related diseases. GR, rendered malfunctional by BAG1, fits nicely into this model. However, the authors used a mouse model that overexpresses the short isoform of BAG1 (2). This isoform has been shown by two groups to not inhibit GR (3, 4). We are not aware of any study that shows an inhibitory function of BAG1S on the transcriptional activity of GR, and the authors do not provide evidence for this. Instead, the longer isoform BAG1M has

www.pnas.org兾cgi兾doi兾10.1073兾pnas.0809354105

been demonstrated to exert an inhibitory influence on GR (3, 4). Thus, there is no evidence that phenotypes related to mania and depression observed in their model of BAG1 overexpression can be correlated to a disturbed GR and stress system. Therefore, it is likely that these mice model the GR- and stress-independent aspects of mania and depression. Ulrike Schmidt, Florian Holsboer, and Theo Rein1 Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany 1. Maeng S, et al. (2008) BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments. Proc Natl Acad Sci USA 105:8766 – 8771. 2. Kermer P, et al. (2003) BAG1 over-expression in brain protects against stroke. Brain Pathol 13:495–506. 3. Schneikert J, Hubner S, Martin E, Cato AC (1999) A nuclear action of the eukaryotic cochaperone RAP46 in downregulation of glucocorticoid receptor activity. J Cell Biol 146:929 –940. 4. Schmidt U, et al. (2003) Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the glucocorticoid receptor. J Biol Chem 278:4926 – 4931.

Author contributions: U.S., F.H., and T.R. wrote the paper. The authors declare no conflict of interest. 1To

whom correspondence should be addressed. E-mail: [email protected].

© 2008 by The National Academy of Sciences of the USA

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