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

Abstract

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.

Figure 1

Analysis of peripheral nerve function. (A) Nerve conduction studies performed on 20 week-old Ercc1^−/Δ mice (gray bars, N=7), normal littermates (black bars, N=4), and 120 week-old controls (open bars, N=3). (B) Nerve conduction studies performed on 8 week-old Ercc1^−/Δ mice (N=3) and normal littermates (N=3). Values represent mean ± SEM. CMAP - sciatic nerve compound muscle action potential, MNCV - sciatic nerve motor nerve conduction velocity, FSA - foot sensory nerve amplitude, FSCV - foot sensory nerve conduction velocity, CNA - caudal nerve amplitude, CNCV - caudal nerve conduction velocity. *p < 0.05 compared to 20 week-old controls.

Figure 2

Peripheral nerve morphology. Representative micrographs from cross sections of the sciatic nerve of a 20 week-old control mouse (A,D), a 20 week-old Ercc1^−/Δ mouse (B,E), and a 120 week-old control mouse (C,F). Notice the well organized appearance and number of larger diameter nerve fibers in the control sections. Compare this with the disorganized and ‘empty’ appearing section from the 20 week-old Ercc1^−/Δ mouse. Morphometric analysis of nerve fiber size distribution (G) and area occupied by nerve fibers, myelin, or endoneurium space (H) in 20 week-old Ercc1^−/Δ mice (gray bars, N=5), 20 week-old control mice (black bars, N=5), and 120 week-old control mice (open bars, N=2). Representative micrographs from cross sections of the sciatic nerve of an 8 week-old Ercc1^−/Δ mouse (J) and age-matched control mouse (I). Bars in (D) and (I) = 50 um. Values represent mean ± SEM. *p < 0.05 compared to 20 week-old controls.

Figure 3

Representative transmission electron micrographs of the sciatic nerve of 20 week-old Ercc1^−/Δ mice. Hallmarks of axonal atrophy can be observed including redundant myelin (a), crenated myelin sheaths (b), myelin droplets (c), myelin ovoid (d), and degenerating axon profiles (e), leading to secondary myeline degeneration evidenced by wide myelin incisures or paranodal loops (f). Bars = 2 μm.