Premature aging-related peripheral neuropathy in a mouse model of progeria
Highlights
► 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.
Introduction
Aging-related peripheral neuropathy contributes significantly to morbidity in the elderly. The prevalence of idiopathic peripheral neuropathy, i.e. neuropathy that is not associated with some underlying disease process such as diabetes, has been reported to be between 19 and 22% in persons aged 60–74 years and up to 58% of people aged 85 and older (Mold et al., 2004, Richardson, 2002). Approximately 14% of adults 65 years or older, and 35% of adults 85 years or older, report difficulty with walking (Resnick et al., 2000). Loss of lower extremity sensory input is associated with impaired balance and falls in the elderly. Indeed, unintentional injury, mostly due to falls, is the sixth leading cause of death in those 65 years of age or older (Sattin, 1992).
Nerve conduction studies (NCS) in humans have shown a progressive decrease in nerve conduction velocities and an increase in the latency of onset of F-waves and provoked sensory nerve responses with advancing age (Bouche et al., 1993, Dorfman and Bosley, 1979, Olney, 1998, Taylor, 1984). Sensory nerve action potential amplitudes appear to decrease at a faster rate than conduction velocities. Morphologic analysis of the sural nerve revealed a progressive loss of both large and small myelinated fiber density with age (Tohgi et al., 1977).
Aging-related changes in peripheral nerves of mice reflect those that have been described in humans. Nerve conduction velocities remain unchanged during adulthood until the last third of life, after which they begin to decline (Verdu et al., 1996). Morphologic examination agrees with this finding as tibial nerves appear to be stable in the adult 6–12 month-old mouse. From 12 to 20 months, there is a gradual decline in the number and density of myelinated and unmyelinated nerve fibers. From 20 months on, there is marked attrition of fibers with approximately 50% loss of myelinated fibers and 35% loss of unmyelinated fibers. This results in a general disorganization of the endoneurium, coupled with an increase in the amount of collagen deposition (Ceballos et al., 1999, Verdu et al., 2000). Along with a loss of fibers, there is a decrease in myelin thickness and decrease in fiber diameter (Ceballos et al., 1999). Furthermore, the fraction of myelinated axons showing irregular shapes increases to 50% in aged mice. These large irregular fibers show abnormalities in the myelin sheath such as wide incisures, separation of lamellae, and myelin loops (Ceballos et al., 1999, Knox et al., 1989).
The molecular basis of aging and aging-related degenerative changes is not known (Kirkwood, 2005). However, it is generally accepted that aging is driven by time-dependent accumulation of stochastic molecular and cellular damage (Campisi and Vijg, 2009, Kirkwood, 2005, Vijg, 2008). Consistent with this, the majority of human progeroid syndromes, or diseases of segmental (tissue-specific) accelerated aging, are caused by defects in genome maintenance mechanisms, including Werner syndrome, ataxia telangiectasia, Cockayne syndrome and trichothiodystrophy (Hasty et al., 2003). This suggests that DNA damage is one type of stochastic molecular damage that promotes aging-related degenerative changes.
Nucleotide excision repair (NER) is an evolutionarily conserved mechanism that removes helix-distorting DNA lesions from the nuclear genome through the coordinated action of over 30 proteins including XPA through XPG, ERCC1, TFIIH and the replication machinery (Friedberg et al., 2006). Mutations in XPF can lead to XFE progeroid syndrome (Niedernhofer et al., 2006), a disease of systemic accelerated aging, or xeroderma pigmentosum (XP), which is primarily a cancer-predisposition syndrome but includes segmental aging (Niedernhofer, 2008a) including progressive peripheral neurodegeneration (Kraemer et al., 2007). The former was modeled in the mouse by creating a hypomorphic mutation in the mErcc1 locus, which encodes ERCC1 the essential binding partner of XPF (Dolle et al., 2006, Weeda et al., 1997). Together ERCC1-XPF form a nuclease that is required for numerous DNA repair mechanisms (Ahmad et al., 2008, Niedernhofer et al., 2004, Sijbers et al., 1996). Ercc1−/Δ mice harboring one knock-out and one mutant allele of Ercc1 express 10% of the normal level of the nuclease ERCC1-XPF. These mice demonstrate spontaneous premature onset of aging-related changes of the epidermal, hematopoietic, endocrine, hepatobiliary, renal, nervous and musculoskeletal identical to XFE progeroid syndrome (Niedernhofer, 2008a) and a maximum lifespan of 32 weeks. In this study we evaluated peripheral nerve structure and function, in Ercc1−/Δ mice to determine if they represent an accelerated model of aging-related peripheral neuropathy that could be used to identify the molecular mechanism of disease and rational strategies for prevention and/or treatment.
Section snippets
Animals
All Ercc1−/Δ mice were generated by matings of heterozygous mice in two different inbred backgrounds to create f1 hybrids that are isogenic: (e.g., Ercc1+/Δ FVB/n X Ercc1+/− C57Bl/6). Genomic DNA was isolated from a 1 mm ear plug of 10–14 day-old mice using a NucleoSpin® 96 Tissue DNA extraction system (Macherey-Nagel, Inc.). Genotyping of the Ercc1 null allele was done by PCR co-amplification of the 3′ end of exon 7 from the wild-type (wt) allele and the neomycin resistance marker cloned into
Results
Ercc1−/Δ mice develop normally until 8 weeks of age, when they begin to spontaneously exhibit progressively worsening degenerative changes associated with old age, including multiple symptoms associated with neurodegeneration (dystonia, trembling and ataxia, at ∼9, 12 and 15 weeks, respectively) (Ahmad et al., 2008, Dolle et al., 2006, Weeda et al., 1997). Nerve conduction studies in twenty week-old Ercc1−/Δ mice, which are symptomatic, demonstrated numerous functional deficits characteristic
Discussion
Aging-related peripheral neuropathy is associated with reductions in both conduction velocity and evoked amplitude response (Verdu et al., 1996). Similar findings were observed in 20 week-old Ercc1−/Δ mice, which are chronologically still young adults (Fig. 1). The nerve conduction studies are supported by morphological evidence of loss of peripheral nerve fibers, in particular large ones (Fig. 2) and abnormal myelin structures indicative of axonal atrophy and myelin degeneration (Fig. 3).
Acknowledgements
This work was supported by the National Institutes of Health grants ES016114 and 03S to L.J.N. and CA076541 to D.B.S., the Ellison Medical Foundation (AG-NS-0303-05; L.J.N.), and Pilot Projects from the University of Pittsburgh Claude B. Pepper Center (P30AG024827; PI: Studenski) and a Pilot the Pittsburgh Center for Kidney Research (P30DK079307; PI Kleyman). P.D.R is supported by National Institutes of Health grants NS058451, AG024827, AG033907 and AR051456. J.C.G. is supported by National
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