Hageman J, Rujano MA, van Waarde MA, Kakkar V, Dirks RP, Govorukhina N, Oosterveld-Hut HM, Lubsen NH, Kampinga HH. A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell. 2010 Feb 12;37(3):355-69. PubMed.
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Massachusetts Institute of Technology
The authors demonstrated nicely that DNAJB6b and DNAJB8, members of DNAJB chaperone subfamily, can potently suppress poly-Q toxicity. The anti-aggregation activity is Hsp70-independent. Histone deacetylase 4 interacts with these DNAJBs and likely regulates their activity through deacetylation. The paper provided an intriguing mechanism for HDAC4 in suppressing cytotoxic protein aggregation. It would be interesting to test this mechanism in a more neuronal relevant system, such as a Huntington disease mouse model. This paper, together with other publications, also suggests that different HDACs could have either neuroprotective or neurotoxic roles, depending on the context. Collectively, these observations imply that development of isoform-selective HDAC inhibitors is necessary.
View all comments by Ling PanThis paper by Jurre Hageman and colleagues provides more data suggesting that global histone deacetylase inhibition (HDACi) is fraught with potential complications, even though the integrated effect of HDACi is obviously beneficial for mice carrying polyQ expansions. It also raises the possibility that the induction of other Hsp chaperones by nuclear HDAC inhibition overcomes the downsides of HDAC4 inhibition.
The field has long moved beyond global HDAC inhibition and has embraced the notion that selective HDAC isoforms, including HDAC2 (Guan et al., 2009), HDAC6 (Rivieccio et al., 2009), and HDAC1, according to a recent paper by Patricio Casaccia and colleagues (Kim et al., 2010), are the way to move forward therapeutically.
HDAC4 is quite an interesting protein, and Santosh D'Mello, Eric Olson, and colleagues have demonstrated a pro-survival role of this molecule, with elegant in vitro and in vivo studies (see Majdzadeh et al., 2008). This function of HDAC4 appears not to depend on its deacylating activity and thus may not be fully abrogated by global HDAC inhibitors. Another very important paper that has been overlooked by the clinical neuroscience community is one by Jun Sadoshima and colleagues which shows that oxidation of HDAC4 moves it to the cytoplasm (Ago et al., 2008). We are currently working on a model by which HDAC4 movement from the nucleus to the cytoplasm could be a mechanism to de-repress or activate adaptive genes in the nucleus while placing HDAC4 in the cytoplasm to partner with DNAJB8 and DNAJB6b.
The notion that small DNAJB proteins are involved in Huntington disease is not new, and elegant papers by Borrell-Pagés (see Borrell-Pagés et al., 2006) a few years ago and by Karpuj and Steinman (see Karpuj et al., 2002) suggest that HSJ1b is repressed transcriptionally by mutant huntingtin. We have a paper in revision at EMBO Molecular Medicine that shows that transglutaminase acts as a nuclear co-repressor for many genes including DNAJB2, the murine homolog of HSJ1b, and that transglutaminase inhibition, molecularly or pharmacologically, can normalize message levels for this important gene. Our findings, in the context of the studies described above, suggest that transglutaminase inhibition, selective HDAC inhibition (leaving HDAC4 unperturbed), or REST inhibition (see Rigamonte et al., 2009) may be viable strategies to optimize DNAJB8 levels in polyglutamine disorders and avoid the problems of global HDAC inhibition.
DNAJB8 appears important not only to limit polyQ toxicity, as shown by this paper, but also to optimize trafficking of BDNF in HD (see Borrell-Pagés et al., 2006).
References:
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