A rare genetic disorder provides insights into mechanisms of early-onset neurodegeneration

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. ### Competing Interest Statement SNZ holds patents on mutational signature-based clinical algorithms not relevant to the research presented in this paper. The other authors declare no competing interests. All other authors declared no competing interest. ### Funding Statement Wellcome PhD fellowship WT216339/Z/19/Z (to S.M) Cancer Research UK (CRUK) Advanced Clinician Scientist Award C60100/A23916 (to S.N.Z) Dr Josef Steiner Cancer Research Award 2019 (to S.N.-Z) Basser Gray Prime Award 2020 (to S.N.-Z) CRUK Pioneer Award C60100/A23433 (to S.N.-Z) CRUK Grand Challenge Award C60100/A25274 (to S.N.-Z) CRUK Early Detection Project Award C60100/A27815 (to S.N.-Z) National Institute of Health Research (NIHR) Research Professorship NIHR301627 (to S.N.Z) NIHR Cambridge Biomedical Research Centre BRC-1215-20014 (to S.N.-Z) CRUK Centre grant C309/A25144 (to T.I.R, J.C) Long-term FEBS fellowship (to L.V.-J) CRUK Programme Foundation award C51061/A27453 (to C.F) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: -Research Ethics Committee in England (REC: Norfolk NRES Committee; REC reference 13/EE/0302)gave ethical approval for this work. -Scotland A Research Ethics Committee (REC reference 14/SS/0096) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors