Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease

Area of Science:

• Genetics and Molecular Biology
• Vascular Biology
• Neuroscience

Background:

• Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, incurable microvascular disease.
• The disease is linked to mutations in the TREX1 gene, encoding a crucial exonuclease enzyme.

Purpose of the Study:

• To investigate the molecular mechanisms underlying RVCL-S pathogenesis.
• To identify potential therapeutic targets for RVCL-S.

Main Methods:

• Analysis of TREX1 sequencing data from UK Biobank participants.
• Evaluation of RVCL-S-related clinical and imaging outcomes.
• Differential proteomics to identify protein interaction changes.
• In vitro studies using endothelial cells with patient mutations.

Main Results:

• Mono-allelic TREX1 truncating mutations require intact nuclease activity to cause endothelial disease.
• Pathogenic TREX1 truncation disrupts interaction with ER insertion proteins, leading to nuclear mislocalization of active TREX1.
• Mislocalized active TREX1 induces DNA damage in endothelial cells.
• Exonuclease inhibition rescues these pathological changes.

Conclusions:

• Exonuclease-dependent DNA damage in endothelial cells is a critical factor in RVCL-S pathogenesis.
• Targeting TREX1 exonuclease activity presents a promising therapeutic strategy for RVCL-S.