How does the Sp3-HDAC2 Complex Reduce Synaptic Function in Alzheimer’s?

Aging


In a recent study, researchers sought to identify proteins important for the anti-neural plasticity effects of histone deacetylase 2 (Hdac2) in Alzheimer’s disease.

How Cells Control Gene Activity

 Acetylation is one method by which cells control gene activity by the addition or removal of acetyl groups. Acetylation is performed by enzymes called acetyltransferases on histone proteins. Acetylation usually causes histone proteins to bind less tightly to a segment of DNA, allowing cellular machinery to read and copy DNA strands. This is a process called transcription.  After the DNA has been copied, cellular machinery can then use the copy as a blueprint to create gene products such as proteins. This is a process called translation.  Proteins then carry out various functions in the body. Deacetylationhas the opposite effect.

HDAC2 Gene Impacts Neuron Function

The HDAC2 gene has been shown to impact the function of neurons by preventing the transcription of genes related to the nervous system. When there is a deficiency of the HDAC2 protein, the HDAC2 gene has positive effects on memory and synaptic plasticity. Synaptic plasticity is the ability of neural connections, or synapses, to strengthen or weaken as necessary. When there is an abundance of the HDAC2 protein, the HDAC2 gene has negative effects on memory and synaptic plasticity.

Of note, HDAC2 tends to be abundant in Alzheimer’s disease (AD) and as such, therapies which specifically target HDAC2 function or prevalence may be useful for treating the cognitive impairments associated with Alzheimer’s disease.

Identifying Essential Genes to HDAC2 Function

In a recent study published in Cell Reports, researchers sought to identify and inhibit the action of genes essential to HDAC2 function. Experiments used mice with or without Alzheimer’s disease.

The researchers first assessed the transcription of genes with products that were suspected to allow HDAC2 to interact with promoters of synaptic plasticity genes. Promoters are regions where transcriptional machinery binds to and starts reading a gene. They found the transcription patterns of the genes SP3, TDP2, and SAP30 to be significantly associated with HDAC2. These three genes produce DNA-binding proteins which reduce the transcription of other genes. The Sp3 and Tdp2 proteins were furthermore found to directly interact with Hdac2.

How Do These Genes Affect Synaptic function?

In order to determine the effect of these genes on synaptic function, researchers measured currents generated by neurons against Hdac2, Sp3, Sap30, or Tdp2 mRNAs.

The reduction in HDAC2 or SP3 translation was associated with increased current frequency and intensity. Further, there was significant overlap in the profile of genes affected by Hdac2 andSp3 mRNA deficiency, suggesting the two genes work in concert. To determine whether HDAC2 and SP3 activity are altered in Alzheimer’s disease, the gene profiles of control and Alzheimer’s disease mice were compared. Many of the genes for which Hdac2 and Sp3 deficiencies caused increase transcription, had decreased transcription in Alzheimer’s disease.

To determine the effect of Alzheimer’s disease (AD) on Sp3 levels, overall levels of Sp3, and HDAC2 and Sp3 levels at promoters, were examined in mice with AD. Sp3 levels were found to be elevated in the hippocampus and cortex of AD mouse brains. Similarly, HDAC2 and Sp3 levels were prevalent in the promoter regions of many of their target genes. To determine the significance of Sp3 levels in AD progression, Sp3 was targeted in the hippocampus of AD mouse brains. Targeting Sp3 improved long-term, but not short-term, strengthening of synapses in AD mice to levels comparable to those seen in control mice.

In examining the structure of HDAC2 to better understand the HDAC2-Sp3 interaction, it was discovered that the carboxyl end of HDAC2 (2C) is chiefly what binds to Sp3. To determine whether an abundance of 2C (which would prevent the formation of functional HDAC2-Sp3 complexes by binding Sp3) affects synaptic function, neurons were exposed to unaltered HDAC2 and a mutant form with extra 2C domains. The currents generated were recorded. Mutant HDAC2 had similar effects on intensity and frequency as targeting Hdac2 or Sp3.

To investigate the therapeutic potential of 2C, the effects of 2C levels on synaptic strengthening was tested in control and Alzheimer’s disease mouse brains.Effects on cognitive function were also tested in live control and Alzheimer’s disease mice administered a fear-based learning test, in which they were expected to freeze in anticipation of discomfort after a stimulus.Increased levels of hippocampal 2C both enhanced long-term synaptic strengthening in Alzheimer’s disease brains and rescued deficits in fear-based learning in Alzheimer’s disease mice.

 HDAC2 and Sp3 Affect Many Genes in Alzheimer’s

The study findings suggest the HDAC2-Sp3 complex is an important modulator of synaptic function. Moreover, HDAC2 and Sp3were found to affect many of the synaptic genes implicated in Alzheimer’s. Evidence was found to support the recruitment of HDAC2 by Sp3 to the promoters of many synaptic genes, enabling it to deacetylate nearby histones and reduce gene transcription. The improvements in long-term synaptic strengthening, synaptic gene expression, and cognitive function observed when Hdac2 or Sp3 were targeted or when Sp3 was bound to abundant, inert 2C suggest the HDAC2-Sp3 complex may serve as a good therapeutic target for the treatment of Alzheimer’s disease.

Written by Raishard Haynes, MBS

Reference:

Yamakawa, H. et al. (2017). The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons. Cell Reports, DOI: http://dx.doi.org/10.1016/j.celrep.2017.07.044



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