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

James R. Goss; Donna Beer Stolz; Andria Rasile Robinson; Mingdi Zhang; Norma Arbujas; Paul D. Robbins; Joseph C. Glorioso; Laura J. Niedernhofer

doi:10.1016/j.mad.2011.04.010

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

James R. Goss, Donna Beer Stolz, Andria Rasile Robinson, Mingdi Zhang, Norma Arbujas, Paul D. Robbins, Joseph C. Glorioso, Laura J. Niedernhofer

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English (US)
Pages (from-to)	437-442
Number of pages	6
Journal	Mechanisms of Ageing and Development
Volume	132
Issue number	8-9
DOIs	https://doi.org/10.1016/j.mad.2011.04.010
State	Published - Aug 2011
Externally published	Yes

Bibliographical note

Funding Information:
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 Institutes of Health grants DK04493 and CA119298.

Keywords

DNA repair
Nerve conduction
Nerve morphology
Neurodegeneration
Progeria
Xeroderma pigmentosum

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10.1016/j.mad.2011.04.010

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title = "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.",

keywords = "DNA repair, Nerve conduction, Nerve morphology, Neurodegeneration, Progeria, Xeroderma pigmentosum",

author = "Goss, {James R.} and Stolz, {Donna Beer} and Robinson, {Andria Rasile} and Mingdi Zhang and Norma Arbujas and Robbins, {Paul D.} and Glorioso, {Joseph C.} and Niedernhofer, {Laura J.}",

note = "Funding Information: 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 Institutes of Health grants DK04493 and CA119298.",

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AU - Robbins, Paul D.

AU - Glorioso, Joseph C.

AU - Niedernhofer, Laura J.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

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