The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Histone deacetylase 2 (HDAC2) is upregulated in Alzheimer's disease (AD) and negatively regulates synaptic plasticity.
• Existing therapeutics targeting HDAC2 have not been successful.
• Identifying proteins mediating HDAC2 recruitment is crucial for developing effective AD treatments.

Purpose of the Study:

• To identify proteins that mediate HDAC2 recruitment to synaptic plasticity genes.
• To explore the therapeutic potential of targeting the HDAC2-Sp3 interaction in AD.

Main Methods:

• Integrative genomics approach to identify interacting proteins.
• Functional screening including gene knockdown and expression studies.
• Assessment of synaptic plasticity and memory in mouse models of neurodegeneration.

Main Results:

• Sp3 was identified as a protein that facilitates HDAC2 recruitment to synaptic genes.
• Sp3 expression is elevated in AD patients and mouse models, similar to HDAC2.
• Knockdown of Sp3 ameliorated synaptic dysfunction in AD models.
• Targeting the HDAC2-Sp3 complex restored synaptic plasticity and memory in mice.

Conclusions:

• The transcription factor Sp3 plays a critical role in HDAC2-mediated regulation of synaptic plasticity.
• Targeting the HDAC2-Sp3 complex represents a promising therapeutic strategy for enhancing cognitive function in Alzheimer's disease.
• This approach may offer a way to improve cognitive function without broadly inhibiting HDAC2 activity.