Neurodegeneration in aging: Lessons from Cockayne Syndrome

Aging is associated with the development of various tissue dysfunctions, such as neurodegenerative diseases. This process is not fully established, mainly due to the difficulty of accessing human neural tissue. One way forward is to study syndromes associated with premature aging that show enhanced cellular processes in in vitro models. Cockayne syndrome (CS) is one such disorder in which individuals have a life expectancy of no more than 20 years, during which they suffer from severe neurological symptoms associated with brain atrophy. At the cellular level, the nucleotide excision repair (NER) pathway is altered, which is known to repair bulky DNA damage, such as those caused by UV light. Mutations in this pathway can also lead to a 10,000-fold increase in skin tumors, but not in CS patientsthe relationship between NER and neurodegeneration is unclear. Here, using induced pluripotent cells derived from dermal fibroblasts of CS patients, we observed a high sensitivity to drugs that oxidize DNA, suggesting that genomic instability in these patients may be caused by reactive species produced by cell metabolism. Furthermore, we differentiated pluripotent cells into neural progenitor cells and mature cultures of neurons and astrocytes. We observed an increase in the number of DNA lesions in these cultures compared to controls shortly after oxidant treatment, suggesting slower repair kinetics in these cells. We also found that this type of DNA damage does not lead to blockage of RNA polymerase, an effect previously thought to be a significant contributor to the severe symptoms of CS. We also observed that DNA damage signaled differently from control cells, an effect that may integrate the molecular basis of disease progression. Furthermore, we developed a tridimensional in vitro model of the cerebral cortex of these patients and observed a marked depletion of neural progenitor regions, an effect that might be associated with CS progression. Finally, in this model, we identify toxic protein deposits associated with aging and dementia, which reinforces the accelerated aging aspect of the syndrome. We hope that with this new 3D model, we can contribute to a better understanding of the mechanisms of CS and provide a platform for therapeutic research, and, more ultimately, offer a model to study age-related neurodegeneration in the general population. (AU)