Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• SORCS2 is a member of the Vps10p-domain receptor family, crucial for neuronal survival, differentiation, and function.
• Genetic studies link SORCS2 to cognitive function and neurodegenerative/psychiatric disorders.
• DNA damage and repair deficits are implicated in aging and neurodegeneration.

Purpose of the Study:

• To investigate the novel role of SORCS2 in DNA double-strand break (DSB) formation.
• To explore the consequences of SORCS2 loss on neuronal DNA integrity and viability.

Main Methods:

• Analysis of DSB levels in the mouse dentate gyrus following Sorcs2 loss.
• Investigating the impact of SORCS2 knockout on Topoisomerase IIβ-dependent DSB formation in a human neuronal cell line.
• Assessing neuronal viability in SORCS2-deficient cells.

Main Results:

• Sorcs2 loss in mice correlated with elevated DSB levels in the dentate gyrus.
• Knocking out SORCS2 in human neuronal cells increased Topoisomerase IIβ-dependent DSB formation.
• SORCS2 deficiency reduced neuronal viability in vitro.
• Neuronal stimulation did not affect DNA break levels in vitro.

Conclusions:

• SORCS2 plays a previously unrecognized role in regulating DNA double-strand break formation.
• SORCS2 deficiency contributes to increased DNA damage and reduced neuronal viability, potentially linking it to neurodegenerative conditions.
• Findings support the connection between VPS10 receptors, DNA damage, and neurodegeneration.