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

Cherif Badja1, Sophie Momen1, Gene Ching Chiek Koh1

  • 1Department of Medical Genetics, Box 238, Level 6, Addenbrooke's Treatment Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0QQ, UK; Early Cancer Institute, Department of Oncology, Box 197, Hutchison Research Centre, Cambridge Biomedical Research Campus, Cambridge CB2 0XZ, UK.

Cell Reports
|May 28, 2024
PubMed

Insights

Xeroderma pigmentosum (XP) patients show neurodegeneration due to DNA repair defects. This study reveals oxidative stress and impaired protein clearance in XP neurons, offering potential therapeutic targets for this rare genetic disorder.

Area of Science:

  • Genetics and Molecular Biology
  • Neuroscience
  • Cellular Biology

Background:

  • Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by defective DNA repair, leading to UV hypersensitivity and increased skin cancer risk.
  • Neurodegeneration and premature death are observed in many XP patients, but the underlying mechanisms remain poorly understood.
  • Understanding the cellular basis of XP neurodegeneration is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the molecular mechanisms driving neurodegeneration in Xeroderma pigmentosum.
  • To utilize patient-derived pluripotent stem cells and multi-omics to analyze neuronal differentiation in XP.
  • To identify potential therapeutic targets for XP-associated neurodegeneration.

Main Methods:

  • Generation and neuronal differentiation of pluripotent stem cells from XP patients and healthy controls.
  • Functional multi-omics analysis (genomics, transcriptomics, proteomics, etc.) during neuronal differentiation.
  • Assessment of DNA damage markers, oxidative stress, endoplasmic reticulum stress, and protein clearance pathways (ubiquitin-proteasome system).

Main Results:

  • XP neurons exhibit significantly elevated levels of 5',8-cyclopurine and 8-oxopurine, indicative of increased oxidative stress.
  • Upregulation of the endoplasmic reticulum stress response was observed in XP neuronal models.
  • XP neurons show a critical downregulation of the ubiquitin-proteasome system (UPS), a key protein clearance pathway.
  • Genetic correction of the XP genotype led to phenotypic rescue in neuronal models.
  • Enhancing UPS activity partially ameliorated phenotypes in XP neuronal models, though not fully resolving the issue.

Conclusions:

  • Oxidative stress and impaired protein degradation via the UPS contribute to neurodegeneration in Xeroderma pigmentosum.
  • The endoplasmic reticulum stress response is implicated in the pathophysiology of XP neurodegeneration.
  • Targeting the UPS and mitigating oxidative stress present potential therapeutic avenues for XP patients, although further research is warranted.
Keywords:
CP: Cell biologyCP: NeuroscienceDNA damageUPSXPearly detectionendoplasmic reticulum stress responseiPSCsneurodegenerationoxidative stressubiquitin-proteasome systemxeroderma pigmentosum

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