. Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48. Sci Transl Med. 2013 Aug 28;5(200):200ra115. PubMed.

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  1. This elegant study by Kandel and colleagues represents a tour-de-force effort to integrate functional genomic studies spanning human post-mortem brain gene expression analysis to mouse models to uncover an important molecule involved in chromatin-mediated neuroplasticity. One that appears to play a key role in age-dependent memory loss.

    What is exciting about this study is that it not only builds on the Kandel, and other laboratories', previous work on the role of CREB/CBP-mediated transcription in memory formation, but it also nicely complements recent findings that have pointed to a key role for the family of zinc-dependent histone deacetylases (HDACs), particularly HDAC2, as memory suppressors that are involved in normal learning and memory and also in neurodegeneration.

    Excitingly, pharmacological inhibitors of this family of HDACs, such our recently described compound crebinostat (Fass et al., 2013), can enhance the transcription of CREB-CBP targeted genes through removing repressive chromatin-modifying activities leading to improved memory in mice. Similarly, selective targeting of HDAC2 with RNAi in the hippocampus can restore memory and the expression of key genes for synaptic plasticity in the context of Alzheimer's disease-like mouse models (Graff et al., 2012). Based upon these findings, drugs selectively targeting HDACs to overcome the loss of RBAP48 may be beneficial for normal age-dependent memory loss in addition to neurodegeneration.

    Additionally, as emphasized by this study on RBAP48, as alternatives to targeting HDACs, the discovery of other pharmacological agents targeting CREB/CBP-mediated transcription, for example through enhancing the acetyltransferase activity of CBP or blocking other components of the co-repressor complexes that antagonize CBP-mediated histone acetylation, may provide new avenues to enhance memory and prevent age-dependent memory loss in normal individuals and in the context of the degenerating brain. Future studies aiming to elucidate the detailed molecular mechanisms through which RBAP48 modulates chromatin-mediated neuroplasticity will hopeful guide such efforts in the near future.

    References:

    . Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity. Neuropharmacology. 2013 Jan;64 Epub 2012 Jul 4 PubMed.

    . An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Mar 8;483(7388):222-6. PubMed.

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