Premature aging-related peripheral neuropathy in a mouse model of progeria

Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue-specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1−/Δ mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1−/Δ mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies.

► Aging related idiopathic peripheral neuropathy is a common disease of unknown etiology.
► DNA repair-deficient Ercc1−/Δ mice spontaneous develop peripheral neuropathy by 5 months.
► Functional and structural changes in their peripheral nerves mimic those that occur with old age.
► This yields new insight on the cause of peripheral neurodegeneration.
► This validates Ercc1−/Δ mice as a rapid and accurate model for screening therapies.