TC NER : Transcription stress Counteracted by Nutritional interventions of Exceptional importance for rare DNA Repair diseases

Rare genome instability syndromes such as Cockayne syndrome (CS) and trichothiodystrophy (TTD) display segmental but dramatic accelerated aging reflecting multi-morbidity in many organs and tissues. The most severe clinical hallmark is neurodegeneration, often limiting life expectancy to childhood and strongly affecting QoL. Unfortunately, presently no cure exists. We have recently found that reducing daily nutrition is of tremendous benefit for DNA repair-deficient progeroid mouse mutants, which very closely mimic the human repair disorders. All features of accelerated aging were unequivocally delayed, and lifespan was extended by 200%, simply by reducing food intake. Most impressive was the effect on neurodegeneration: instead of slowing down or halting signs of severe neurodysfunction, tremors and imbalance even disappeared, revealing significant improvement (Vermeij et al., Nature 2016). Clinical observations from one TTD (XPD) patient has recently provided additional and consistent data: when parents chose to partially reduce caloric intake in their child, motor and cognition improvement has been observed including reduced tremors, improved balance and walking. Within this consortium we aim to mechanistically understand the interplay between nutrition, metabolism, transcription stress and neuronal functioning and explore effects in other rare genome instability syndromes (e.g. ataxia telangiectasia, Fanconi anemia). These aspects will be studied at multiple levels (e.g. cells, organoids, mouse models, cells from patients) to provide improved evidence-based advice.