A rare genetic disorder provides insights into mechanisms of early-onset neurodegeneration
Badja, C.; Momen, S.; Koh, G. C. C.; Boushaki, S.; Roumeliotis, T. I.; Kozik, Z.; Jones, I.; Bousgouni, V.; Dias, J. M. L.; Krokidis, M.; Young, J.; Chen, H.; Yang, M.; Docquier, F.; Memari, Y.; Valcarcel-Jimenez, L.; Gupta, K.; Kong, L. R.; Fawcett, H.; Robert, F.; Zhao, S.; Degasperi, A.; Davies, H.; Harris, R.; Frezza, C.; Chatgilialoglu, C.; Sarkany, R.; Lehmann, A.; Bakal, C.; Choudhary, J.; Fassihi, H.; Nik-Zainal, S.
Show abstract
Xeroderma pigmentosum (XP) is characterized by defective repair of ultraviolet radiation(UVR)-induced DNA damage. Patients have UVR hypersensitivity and increased skin cancer risk. Effective photoprotection has reduced childhood cancer-related deaths, but revealed adolescence-onset neurodegeneration, arising through unknown mechanisms. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We find endoplasmic reticulum stress is upregulated, preceded by oxidative stress, causing substantial 5,8-cyclopurine and 8-oxopurine DNA damage. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.
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