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

被引：1

作者：

Badja, Cherif ^{[1
,2
]}

Momen, Sophie ^{[1
,2
]}

Koh, Gene Ching Chiek ^{[1
,2
]}

Boushaki, Soraya ^{[1
,2
]}

Roumeliotis, Theodoros I. ^{[1
,3
]}

Kozik, Zuza ^{[1
,3
]}

Jones, Ian ^{[4
]}

Bousgouni, Vicky ^{[4
]}

Dias, Joao M. L. ^{[1
,2
]}

Krokidis, Marios G. ^{[5
,6
]}

Young, Jamie ^{[1
,2
]}

Chen, Hongwei ^{[7
,8
]}

Yang, Ming ^{[9
]}

Docquier, France ^{[1
]}

Memari, Yasin ^{[1
,2
]}

Valcarcel-Zimenez, Lorea ^{[9
]}

Gupta, Komal ^{[9
]}

Kong, Li Ren ^{[9
,11
,12
]}

Fawcett, Heather ^{[13
]}

Robert, Florian ^{[2
]}

Zhao, Salome ^{[2
]}

Degasperi, Andrea ^{[2
]}

Kumar, Yogesh ^{[2
]}

Davies, Helen ^{[2
]}

Harris, Rebecca ^{[1
]}

Frezza, Christian ^{[10
]}

Chatgilialoglu, Chryssostomos ^{[14
,15
]}

Sarkany, Robert ^{[16
]}

Lehmann, Alan ^{[11
]}

Bakal, Chris ^{[2
,4
]}

Choudhary, Jyoti ^{[1
,3
]}

Fassihi, Hiva ^{[14
]}

Nik-Zainal, Serena ^{[1
,2
]}

机构：

[1] Addenbrookes Treatment Ctr, Dept Med Genet, Box 238,Level 6,Cambridge Biomed Res Campus, Cambridge CB2 0QQ, England

[2] Hutchison Res Ctr, Early Canc Inst, Dept Oncol, Box 197,Cambridge Biomed Res Campus, Cambridge CB2 0XZ, England

[3] Chester Betty Labs, Inst Canc Res, Funct Prote Grp, 237 Fulham Rd, London SW3 6JB, England

[4] Inst Canc Res, Dynam Cell Syst Lab, Div Canc Biol, 237 Fulham Rd, London SW3 6JB, England

[5] NCSR Demokritos, Inst Nanosci & Nanotechnol, Agia Paraskevi Attikis, Athens 15310, Greece

[6] Ionian Univ, Dept Informat, Bioinformat & Human Electrophysiol Lab, Corfu 49100, Greece

[7] Wellcome Sanger Inst, Hinxton CB10 1EQ, England

[8] Nanjing Univ, Med Sch, Affiliated Drum Tower Hosp, Dept Rheumatol & Immunol, Nanjing 210008, Peoples R China

[9] Univ Cambridge, Med Res Council Canc Unit, Cambridge Biomed Campus, Cambridge CB2 0XZ, England

[10] Univ Hosp Cologne, Fac Med, CECAD Res Ctr, Joseph Stelzmann Str 26, D-50931 Cologne, Germany

[11] Natl Univ Singapore, NUS Ctr Canc Res, Yong Loo Lin Sch Med, Dept Pharmacol, N2CR, Singapore 117599, Singapore

[12] Canc Sci Inst Singapore, Singapore 117599, Singapore

[13] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, England

[14] CNR, Ist Sintesi Organ & Fotoreatt, Via P Gobetti 101, I-40129 Bologna, Italy

[15] Adam Mickiewicz Univ, Ctr Adv Technol, PL-61614 Poznan, Poland

[16] Guys & St Thomas Fdn Trust, St Johns Inst Dermatol, Natl Xeroderma Pigmentosum Serv, London SE1 7EH, England

来源：

CELL REPORTS | 2024年 / 43卷 / 06期

基金：

美国国家卫生研究院;

关键词：

UNFOLDED PROTEIN RESPONSE; DNA-DAMAGE; EXCISION-REPAIR; TRANSMEMBRANE PROTEIN; OXIDATIVE DAMAGE; PATHWAY; INDUCTION; ROLIPRAM; DISEASE; LESIONS;

D O I：

10.1016/j.celrep.2024.114243

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：27