Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency

Area of Science:

• Molecular Biology
• Genetics
• Gerontology

Background:

• The endonuclease XPG is crucial for Nucleotide Excision Repair (NER) of DNA lesions.
• XPG defects cause severe human disorders like xeroderma pigmentosum, Cockayne Syndrome, and COFS syndrome.
• The complex genotype-phenotype relationships in XPG deficiency are not fully understood.

Purpose of the Study:

• To develop and characterize a novel conditional Xpg-/- mouse model.
• To investigate the cell-autonomous role of XPG in aging and neurodegeneration.
• To elucidate the tissue-specific contributions to XPG deficiency phenotypes.

Main Methods:

• Generation of a conditional Xpg-/- mouse model on a mixed genetic background.
• Analysis of progeroid features, including growth, fat loss, skeletal and retinal degeneration, and lifespan.
• Conditional deletion of XPG in specific tissues (liver, forebrain neurons/glia) to assess cell-autonomous effects.

Main Results:

• The Xpg-/- mouse model exhibits significant progeroid features and a shortened lifespan.
• Liver-specific XPG deletion caused liver aging but not systemic effects on growth or lifespan.
• Neuron and glia-specific XPG deletion induced progressive neurodegeneration, mimicking human XPG deficiency.
• Findings support a cell-autonomous origin of XPG deficiency phenotypes.

Conclusions:

• The Xpg-/- mouse is a valid model for severe human XPG deficiency and segmental accelerated aging.
• DNA repair defects, specifically XPG deficiency, are directly linked to aging processes.
• This study enables the dissection of aging into tissue- and cell-type-specific components.