Individuals with the genetic condition xeroderma pigmentosum (XP) have a deficiency in the nucleotide excision repair (NER) mechanism, which leads to exaggerated sunburn and malignant skin lesions. Clinical interventions such as photoprotection and regular dermatological and ophthalmological surveillance have significantly reduced the mortality associated with malignant lesions in these individuals. However, some adult patients with XP may develop neurodegeneration and early-onset dementia.
In an international collaboration involving leading research institutions in the UK and Europe, Dr. Kong Li Ren and colleagues are working to understand the underlying mechanisms using a multi-omics approach, including transcriptomic, genomic, and metabolomic analyses. They first performed neuronal-directed differentiation using human induced pluripotent stem cells (hIPSCs) derived from patients and healthy relatives. In a time-course experiment covering different stages of neuronal differentiation, hIPSCs from XP individuals at high risk for neurodegeneration showed increased ER stress and oxidative DNA damage. This finding highlights the importance of early detection of high-risk individuals, and the study team has proposed a panel of proteomic markers for further validation.
For more details: https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00571-0