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Age-related atrophy of motor axons in mice deficient in the mid-sized neurofilament subunit.

Elder GA, Friedrich VL, Margita A, Lazzarini RA - J. Cell Biol. (1999)

Bottom Line: The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology.By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments.These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.

ABSTRACT
Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a mutation in the heavy neurofilament subunit (NF-H). Mice with mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M- mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

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Time course of changes in ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L5 ventral roots from wild-type (A, D, and G), NF-M– mutant (B, E, and H), and NF-M/H– mutant (C, F, and I) at 4 mo (A–C), 1 yr (D–F), or 2 yr (G–I) of age. Myelinated axons in the ventral roots of the 4-mo- and 1-yr-old NF-M– and NF-M/H–deficient animals, although reduced in size, are otherwise normal in appearance. By contrast, axons in the ventral roots of the 2-yr-old NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. Bar, 10 μm.
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Figure 6: Time course of changes in ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L5 ventral roots from wild-type (A, D, and G), NF-M– mutant (B, E, and H), and NF-M/H– mutant (C, F, and I) at 4 mo (A–C), 1 yr (D–F), or 2 yr (G–I) of age. Myelinated axons in the ventral roots of the 4-mo- and 1-yr-old NF-M– and NF-M/H–deficient animals, although reduced in size, are otherwise normal in appearance. By contrast, axons in the ventral roots of the 2-yr-old NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. Bar, 10 μm.

Mentions: To determine the time course of the axonal atrophy in the ventral roots we examined six 1-yr-old NF-M– and four 1-yr-old NF-M/H– mutants. Fig. 6 shows a comparison of the appearance of ventral root axons from 4-mo-, 1-yr-, and 2-yr-old wild-type and mutant animals. As expected, myelinated axons in 1-yr-old NF-M and NF-M/H animals appeared smaller than 1-yr-old control (Fig. 6, D–F). However, the axons appeared relatively normal in shape and we did not observe any definite pathological changes like those seen in 2-yr-old ventral roots (Fig. 6, G–I) in any of 42 ventral roots collected from 1-yr-old NF-M or in 24 roots from the NF-M/H animals. Thus, the atrophy is predominantly occurring after 1 yr of age. Quantitative longitudinal data on L5 ventral roots from wild-type, NF-M–, and NF-M/H– mutant animals is presented in Table . Most remarkably, these data show that whereas a significant expansion of axonal caliber occurs between 4 mo and 1 yr of age in wild-type animals, axons in the NF-M– mutant expand only slightly and axons in NF-M/H– mutant roots do not expand at all. Wild-type as well as NF-M– and NF-M/H–mutant axons then all undergo varying degrees of age related atrophy between one and two years of age. Interestingly, on a percentage basis the atrophy in the L5 roots between 1 and 2 yr of age in the NF-M– and NF-M/H– mutants is actually slightly less than wild-type. However, the lower base from which the mutants start at one year causes these smaller percentage changes to have a significant absolute effect on axonal caliber at 2 yr.


Age-related atrophy of motor axons in mice deficient in the mid-sized neurofilament subunit.

Elder GA, Friedrich VL, Margita A, Lazzarini RA - J. Cell Biol. (1999)

Time course of changes in ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L5 ventral roots from wild-type (A, D, and G), NF-M– mutant (B, E, and H), and NF-M/H– mutant (C, F, and I) at 4 mo (A–C), 1 yr (D–F), or 2 yr (G–I) of age. Myelinated axons in the ventral roots of the 4-mo- and 1-yr-old NF-M– and NF-M/H–deficient animals, although reduced in size, are otherwise normal in appearance. By contrast, axons in the ventral roots of the 2-yr-old NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. Bar, 10 μm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199745&req=5

Figure 6: Time course of changes in ventral roots of old NF- mutant animals. Light microscopy of toluidine blue–stained cross sections of L5 ventral roots from wild-type (A, D, and G), NF-M– mutant (B, E, and H), and NF-M/H– mutant (C, F, and I) at 4 mo (A–C), 1 yr (D–F), or 2 yr (G–I) of age. Myelinated axons in the ventral roots of the 4-mo- and 1-yr-old NF-M– and NF-M/H–deficient animals, although reduced in size, are otherwise normal in appearance. By contrast, axons in the ventral roots of the 2-yr-old NF-M– and NF-M/H– mutants appear shrunken and frequently irregular in shape. Bar, 10 μm.
Mentions: To determine the time course of the axonal atrophy in the ventral roots we examined six 1-yr-old NF-M– and four 1-yr-old NF-M/H– mutants. Fig. 6 shows a comparison of the appearance of ventral root axons from 4-mo-, 1-yr-, and 2-yr-old wild-type and mutant animals. As expected, myelinated axons in 1-yr-old NF-M and NF-M/H animals appeared smaller than 1-yr-old control (Fig. 6, D–F). However, the axons appeared relatively normal in shape and we did not observe any definite pathological changes like those seen in 2-yr-old ventral roots (Fig. 6, G–I) in any of 42 ventral roots collected from 1-yr-old NF-M or in 24 roots from the NF-M/H animals. Thus, the atrophy is predominantly occurring after 1 yr of age. Quantitative longitudinal data on L5 ventral roots from wild-type, NF-M–, and NF-M/H– mutant animals is presented in Table . Most remarkably, these data show that whereas a significant expansion of axonal caliber occurs between 4 mo and 1 yr of age in wild-type animals, axons in the NF-M– mutant expand only slightly and axons in NF-M/H– mutant roots do not expand at all. Wild-type as well as NF-M– and NF-M/H–mutant axons then all undergo varying degrees of age related atrophy between one and two years of age. Interestingly, on a percentage basis the atrophy in the L5 roots between 1 and 2 yr of age in the NF-M– and NF-M/H– mutants is actually slightly less than wild-type. However, the lower base from which the mutants start at one year causes these smaller percentage changes to have a significant absolute effect on axonal caliber at 2 yr.

Bottom Line: The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology.By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments.These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.

ABSTRACT
Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a mutation in the heavy neurofilament subunit (NF-H). Mice with mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M- mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M- mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

Show MeSH
Related in: MedlinePlus