New study may lead to novel HDAC2 inhibitors for treatment of Alzheimer's disease
Scientists have successfully reversed memory loss in a mouse model of Alzheimer's disease (AD) by selectively inhibiting the enzyme HDAC2.
The study, titled "The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons," appeared in the journal Cell Reports on August 8, 2017.
HDAC2 is one of the multiple histone deacetylases (HDACs) found in the body. HDACs are a class of enzymes that modify histones (proteins that package the DNA), cause the histones to warp the DNA more tightly and therefore inhibit expression of the genes in that segment of DNA. HDAC2 has been identified as a critical negative regulator of synaptic gene expression and neuronal plasticity, which are both important for memory formation. Additionally, previous studies have shown that HDAC2 is increased in AD patient brains and in AD mouse models, and inhibition of HDAC2 leads to improved memory in mouse models. Thus, targeting HDAC2 is considered a promising way to restore cognitive functions in AD. However, despite numerous efforts, there are still no HDAC2-specific inhibitors. Previously developed HDAC inhibitors often also target other members of the HDAC family like HDAC1, and can trigger adverse side effects.
To solve this problem, a team of researchers headed by Li-Huei Tsai from Massachusetts Institute of Technology sought to determine how HDAC2 regulates memory related genes and other molecules involved in this regulation. Using weighted gene co-expression network analysis (WGCNA) and functional analysis, the researchers identified Sp3 as a major partner of HDAC2 action.
Sp3, or called Sp3 transcription factor, is a protein that regulates gene transcription. As is known, HDAC2 and other HDACs can not directly bind DNA. This study showed that Sp3 recruits HDAC2 to synaptic genes, and like HDAC2, Sp3 also negatively regulates the expression of synaptic genes.
Next, the researchers analyzed existing gene expression data of AD patients and healthy controls and examined Sp3 levels in mouse models. The results showed that both HDAC2 and Sp3 are elevated in AD patients and mouse models, and like HDAC2, inhibition of Sp3 also reduced synaptic abnormalities in mouse models.
Finally, the team determined which domain in the HDAC2 protein attaches to Sp3. Overexpression of a protein fragment containing that domain in neurons inhibited the interaction of HDAC2 with Sp3, allowing memory related genes to express. Importantly, overexpression of that domain did not affect the proliferation of mouse embryonic fibroblasts. Furthermore, when the researchers over expressed the domain in the brain of mouse models of neurodegeneration, it counteracted synaptic and cognitive deficits in the animals.
In conclusion, the study shows that inhibiting HDAC2-Sp3 interaction may be a proper way to prevent HDAC2 from blocking memory related gene expression and therefore improve cognitive function.
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