Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system.

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ICR Authors

Roumeliotis, Theodoros
 Bakal, Christopher

Authors

Badja, C
Momen, S
Koh, GCC
Boushaki, S
Roumeliotis, TI
Kozik, Z
Jones, I
Bousgouni, V
Dias, JML
Krokidis, MG
Young, J
Chen, H
Yang, M
Docquier, F
Memari, Y
Valcarcel-Zimenez, L
Gupta, K
Kong, LR
Fawcett, H
Robert, F
Zhao, S
Degasperi, A
Kumar, Y
Davies, H
Harris, R
Frezza, C
Chatgilialoglu, C
Sarkany, R
Lehmann, A
Bakal, C
Choudhary, J
Fassihi, H
Nik-Zainal, S

Document Type

Journal Article

Date

2024-06-25

Date Accepted

2024-05-02

Abstract

Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. 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 show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.

Citation

Cell Reports, 2024, 43 (6), pp. 114243 -

DOI

10.1016/j.celrep.2024.114243

URI

https://repository.icr.ac.uk/handle/internal/6451

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Cell Reports

Publisher

CELL PRESS

ISSN

2211-1247

eISSN

2211-1247

Collections

Cell and Molecular Biology

Research Team

Functional Proteomics
Dynamical Cell Systems

Notes