The DNA repair protein DNA-PKcs modulates synaptic plasticity via PSD-95 phosphorylation and stability

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• DNA-PKcs is a key DNA repair enzyme with known roles in immune and nervous systems.
• Mutations in the PRKDC gene cause severe neurological deficits in humans, suggesting uncharacterized neuronal functions.
• Previous research indicated DNA-PKcs importance in brain development and function.

Purpose of the Study:

• To investigate the role of DNA-PKcs in synaptic plasticity and neuronal function.
• To elucidate the molecular mechanisms by which DNA-PKcs influences neuronal processes.
• To explore the physiological functions of DNA-PKcs in the nervous system beyond its DNA repair role.

Main Methods:

• Localization studies of DNA-PKcs at neuronal synapses.
• Phosphorylation analysis of PSD-95 by DNA-PKcs at novel residues.
• Phenotypic characterization of DNA-PKcs knockout mice, including electrophysiology and morphological analysis.
• Rescue experiments using a constitutively phosphorylated PSD-95 mutant.

Main Results:

• DNA-PKcs was found to localize at synapses and phosphorylate PSD-95, affecting its protein stability.
• DNA-PKcs knockout mice exhibited impaired Long-Term Potentiation (LTP), altered neuronal morphology, and reduced postsynaptic proteins.
• Overexpression of a modified PSD-95 rescued the LTP impairment in DNA-PKcs knockout mice.
• Novel phosphorylation sites on PSD-95 regulated by DNA-PKcs were identified.

Conclusions:

• DNA-PKcs plays a critical, previously unrecognized role in regulating synaptic plasticity and neuronal function.
• The phosphorylation of PSD-95 by DNA-PKcs is a key mechanism underlying its effects on neuronal plasticity.
• This study expands the known physiological functions of DNA-PKcs, extending beyond genome stability to neural plasticity.