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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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Neurofilament content in aging NF-M–deficient animals. (A) NFs were counted in myelinated axons from L5 ventral roots of 2-yr-old wild-type and control animals. The number of NFs in each axon was plotted against axonal size (area in square microns). Note that in myelinated axons of similar size the wild-type has more NFs than the NF-M– mutant. Regression equations:  and .  for effect of genotype on combined slope plus intercept. (B and C) NF densities were determined using methods similar to those described by Price et al. 1988. A template of hexagons was applied over each electron micrograph and the number of NFs per hexagon counted in alternate hexagons. Hexagons were excluded only if vesicular organelles filled more than ∼10% of the hexagon. At least 300 hexagons each equivalent to an area of 0.10 square microns were counted for each group and a frequency distribution plot was generated showing the number of NFs per hexagon. In B, NF densities in ventral root axons are shown for 4-mo- and 2-yr-old NF-M– mutants and 2-yr-old wild-type animals. The average number of NFs per hexagon was 18.0 ± 7.3 (SD) in 2-yr-old control axons, 6.2 ± 4.5 in 2-yr-old NF-M– mutant and 8.5 ± 4.5 in 4-mo-old NF-M– mutant axons (P < 0.0001 for both mutants vs. control and for 4-mo-old vs. 2-yr-old mutants). In C, NF densities are compared in dorsal and ventral root axons of 2-yr-old NF-M– mutants. Values were 9.3 ± 5.8 NFs per hexagon in the 2-yr-old dorsal roots and 6.2 ± 4.5 in 2-yr-old ventral roots (P < 0.0001).
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Figure 4: Neurofilament content in aging NF-M–deficient animals. (A) NFs were counted in myelinated axons from L5 ventral roots of 2-yr-old wild-type and control animals. The number of NFs in each axon was plotted against axonal size (area in square microns). Note that in myelinated axons of similar size the wild-type has more NFs than the NF-M– mutant. Regression equations: and . for effect of genotype on combined slope plus intercept. (B and C) NF densities were determined using methods similar to those described by Price et al. 1988. A template of hexagons was applied over each electron micrograph and the number of NFs per hexagon counted in alternate hexagons. Hexagons were excluded only if vesicular organelles filled more than ∼10% of the hexagon. At least 300 hexagons each equivalent to an area of 0.10 square microns were counted for each group and a frequency distribution plot was generated showing the number of NFs per hexagon. In B, NF densities in ventral root axons are shown for 4-mo- and 2-yr-old NF-M– mutants and 2-yr-old wild-type animals. The average number of NFs per hexagon was 18.0 ± 7.3 (SD) in 2-yr-old control axons, 6.2 ± 4.5 in 2-yr-old NF-M– mutant and 8.5 ± 4.5 in 4-mo-old NF-M– mutant axons (P < 0.0001 for both mutants vs. control and for 4-mo-old vs. 2-yr-old mutants). In C, NF densities are compared in dorsal and ventral root axons of 2-yr-old NF-M– mutants. Values were 9.3 ± 5.8 NFs per hexagon in the 2-yr-old dorsal roots and 6.2 ± 4.5 in 2-yr-old ventral roots (P < 0.0001).

Mentions: NFs were plentiful in the control and NF-H– mutant axons (Fig. 3). Also as expected, axons in the 2-yr-old NF-M/H animals were essentially devoid of NFs. Axons in atrophic roots of old NF-M– mutant animals contained relatively normal appearing NFs. However, NF numbers appeared even more dramatically depleted than in axons of young NF-M– mutants. To quantify the effect on NF number in the old NF-M– mutant, NFs were counted in the internodal regions of axons over a range of sizes and NF counts were plotted against axonal area. As shown in Fig. 4 A, axons in the mutant consistently contained vastly fewer NFs than axons in controls with the mutant axons having only ∼20% as many NFs as a comparably sized wild-type axons.


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)

Neurofilament content in aging NF-M–deficient animals. (A) NFs were counted in myelinated axons from L5 ventral roots of 2-yr-old wild-type and control animals. The number of NFs in each axon was plotted against axonal size (area in square microns). Note that in myelinated axons of similar size the wild-type has more NFs than the NF-M– mutant. Regression equations:  and .  for effect of genotype on combined slope plus intercept. (B and C) NF densities were determined using methods similar to those described by Price et al. 1988. A template of hexagons was applied over each electron micrograph and the number of NFs per hexagon counted in alternate hexagons. Hexagons were excluded only if vesicular organelles filled more than ∼10% of the hexagon. At least 300 hexagons each equivalent to an area of 0.10 square microns were counted for each group and a frequency distribution plot was generated showing the number of NFs per hexagon. In B, NF densities in ventral root axons are shown for 4-mo- and 2-yr-old NF-M– mutants and 2-yr-old wild-type animals. The average number of NFs per hexagon was 18.0 ± 7.3 (SD) in 2-yr-old control axons, 6.2 ± 4.5 in 2-yr-old NF-M– mutant and 8.5 ± 4.5 in 4-mo-old NF-M– mutant axons (P < 0.0001 for both mutants vs. control and for 4-mo-old vs. 2-yr-old mutants). In C, NF densities are compared in dorsal and ventral root axons of 2-yr-old NF-M– mutants. Values were 9.3 ± 5.8 NFs per hexagon in the 2-yr-old dorsal roots and 6.2 ± 4.5 in 2-yr-old ventral roots (P < 0.0001).
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Figure 4: Neurofilament content in aging NF-M–deficient animals. (A) NFs were counted in myelinated axons from L5 ventral roots of 2-yr-old wild-type and control animals. The number of NFs in each axon was plotted against axonal size (area in square microns). Note that in myelinated axons of similar size the wild-type has more NFs than the NF-M– mutant. Regression equations: and . for effect of genotype on combined slope plus intercept. (B and C) NF densities were determined using methods similar to those described by Price et al. 1988. A template of hexagons was applied over each electron micrograph and the number of NFs per hexagon counted in alternate hexagons. Hexagons were excluded only if vesicular organelles filled more than ∼10% of the hexagon. At least 300 hexagons each equivalent to an area of 0.10 square microns were counted for each group and a frequency distribution plot was generated showing the number of NFs per hexagon. In B, NF densities in ventral root axons are shown for 4-mo- and 2-yr-old NF-M– mutants and 2-yr-old wild-type animals. The average number of NFs per hexagon was 18.0 ± 7.3 (SD) in 2-yr-old control axons, 6.2 ± 4.5 in 2-yr-old NF-M– mutant and 8.5 ± 4.5 in 4-mo-old NF-M– mutant axons (P < 0.0001 for both mutants vs. control and for 4-mo-old vs. 2-yr-old mutants). In C, NF densities are compared in dorsal and ventral root axons of 2-yr-old NF-M– mutants. Values were 9.3 ± 5.8 NFs per hexagon in the 2-yr-old dorsal roots and 6.2 ± 4.5 in 2-yr-old ventral roots (P < 0.0001).
Mentions: NFs were plentiful in the control and NF-H– mutant axons (Fig. 3). Also as expected, axons in the 2-yr-old NF-M/H animals were essentially devoid of NFs. Axons in atrophic roots of old NF-M– mutant animals contained relatively normal appearing NFs. However, NF numbers appeared even more dramatically depleted than in axons of young NF-M– mutants. To quantify the effect on NF number in the old NF-M– mutant, NFs were counted in the internodal regions of axons over a range of sizes and NF counts were plotted against axonal area. As shown in Fig. 4 A, axons in the mutant consistently contained vastly fewer NFs than axons in controls with the mutant axons having only ∼20% as many NFs as a comparably sized wild-type axons.

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