The histone deacetylase HDAC2, which negatively regulates neuronal plasticity and synaptic gene expression, is upregulated both in Alzheimers disease (AD) patients and mouse models (Graff et al., 2012). Therapeutics targeting HDAC2 are speculated to be a promising avenue for ameliorating AD related cognitive impairment. However, attempts to generate HDAC2-specific inhibitors have not been successful. Here, we take a novel approach utilizing integrative genomics to identify proteins that mediate HDAC2 recruitment to synaptic plasticity genes. Functional screening revealed that knockdown of the transcription factor Sp3 phenocopied HDAC2 knockdown, and that Sp3 facilitated the recruitment of HDAC2 to synaptic genes. Importantly, like HDAC2, Sp3 expression was elevated in AD patients and mouse models, where Sp3 knockdown ameliorated synaptic dysfunction. Furthermore, exogenous expression of an HDAC2 fragment containing the Sp3 binding domain fully restored synaptic plasticity and memory in a mouse model with severe neurodegeneration. Our findings indicate that targeting the HDAC2-Sp3 complex could enhance synaptic and cognitive function, without affecting HDAC2 function in other processes. SOURCE: Li-Huei Tsai (lhtsai_geo@hotmail.com) - Li-Huei Tsai MIT

Pluto Bioinformatics

GSE87441: The transcription factor Sp3 cooperates with HDAC2 to regulate synaptic function and plasticity in neurons