Beyond Genes: Treating Memory Loss with Minimum Adverse Effects

By Jamshed Arslan Pharm.D.
Research Associate, University of Alabama, Birmingham

Alzheimer's disease (AD) robs people of their memory and identity. One characteristic feature of AD is the increased expression of the enzyme, histone deacetylase-2 (HDAC-2). This protein stops the expression of some memory-forming genes by condensing them. So, memory can be enhanced by inhibiting HDAC-2. However, this approach is dangerous since HDAC-1, a close family member of HDAC-2, would also become inhibited, resulting in neuronal death and other toxic effects. New research,[1] led by Li-Huei Tsai at the Massachusetts Institute of Technology, Cambridge, suggests a novel way to specifically repress HDAC-2 by targeting the domain of HDAC-2 that makes a complex with the transcription factor, Sp3.

HDACs interact with different binding partners to regulate gene expression. Tsai's team sought to identify specific proteins that recruit HDAC-2 to memory-related genes. Researchers identified these proteins through weighted gene co-expression network analysis (WGCNA), which detects genetic correlational patterns across microarray samples. Binding of candidate proteins (co-regulators) to HDAC-2 was confirmed via immunoprecipitation assays. Knockdown of identified co-regulators in cultured mouse neurons was then used to elucidate their role in regulating synaptic function. It turns out that only the knockdown of Sp3 produced a synaptic effect similar to that seen with Hdac-2-knockdown, resulting in improved synaptic plasticity and memory.

Tsai's team had previously shown[2] that inhibiting Hdac-2 in the hippocampi of mice with AD-like symptoms improved synaptic transmission. In the current study,[1] RNA sequence analysis from mice neurons revealed that knockdown of Sp3 upregulates virtually the same memory-related genes that are targeted for inhibition by Hdac-2. Chromatin immunoprecipitation assays indicated that Sp3 knockdown reduces recruitment of Hdac-2 to the promoters of synaptic genes. Reversing the upregulation of Sp3 inhibited Hdac-2 in AD model mice, restoring the expression of Hdac-2 target genes. In line with these findings, the hippocampi of AD patients were found to have increased expression of both Sp3 and HDAC-2. Together, these studies on mice and humans show that Sp3 recruits HDAC-2 to the promoters of genes involved in memory, where HDAC-2 inhibits their expression.

Once it was clear that HDAC-2 and Sp3 co-regulate the same genes implicated in AD, researchers generated a peptide inhibitor that could disrupt the HDAC-2-Sp3 complex formation. Successful inhibition of the complex enhanced synaptic function in neurons, and improved memory in mice without damaging vital cell functions. Only the future will tell if this peptide-inhibitor approach would be effective at the clinic. However, the discovery of a clear role of Sp3 in cognition opens new avenues for drug targeting with minimal side effects.

This is the first study to use WGCNA to detect co-regulators of HDAC-2. In this way, Tsai's team has paved the way for applying bioinformatics and functional assays to other epigenetic regulators and tissues.

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References

1. Yamakawa, Hidekuni, et al. "The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons." Cell Reports, vol. 20, no. 6, 2017, pp. 1319–1334.
2. Gräff, Johannes, et al. "An epigenetic blockade of cognitive functions in the neurodegenerating brain." Nature, vol. 483, no. 7388, 2012, pp. 222–226.        

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