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. 1998 Aug 4;95(16):9631-6.
doi: 10.1073/pnas.95.16.9631.

Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant

T L Williamson  1 , L I Bruijn, Q Zhu, K L Anderson, S D Anderson, J P Julien, D W Cleveland
Affiliations

Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant

T L Williamson et al. Proc Natl Acad Sci U S A. .

Abstract

Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1(G85R) mutant-mediated toxicity to motor neurons.

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Figures

Figure 1
Figure 1
(A) The two-step mating scheme used to produce SOD1G85R, NF-L −/− mice. (B) Immunoblot of 20-μg spinal cord extracts made by using an antibody that recognizes mouse and human SOD1G85R with equal affinity. (C) Parallel Coomassie blue-stained gel demonstrating comparable protein loading. (D and E) Coomassie blue-stained SDS/PAGE gel (D) and immunoblots (E) to measure NF-H and NF-L in 20 μg of sciatic nerve or spinal cord from wild-type mice and heterozygous NF-L and homozygous NF-L knockout mice.
Figure 2
Figure 2
Delayed disease onset and increased survival in SOD1G85R mice lacking neurofilaments. Kaplan–Meier curves showing age of onset (A) and survival (B) of SOD1G85R mice in the presence or absence of neurofilaments.
Figure 3
Figure 3
Reduced motor axon loss, but increased sensory loss, in SOD1G85R mice lacking neurofilaments. Ventral (A–C) and dorsal (G–I) L5 roots from wild-type, NF-L +/−, and NF-L −/− mice, respectively. Ventral (D–F) and dorsal (J–L) L5 roots from end-stage NF-L +/+, NF-L +/−, or NF-L −/− mice expressing the SOD1G85R transgene. (Scale bar, 20 μm.)
Figure 4
Figure 4
Histograms to show the reduced motor axon loss (A and C), but increased sensory loss (B and C) in SOD1G85R mice lacking neurofilaments. The total number of axons (A and B) or the number of degenerating axonal profiles (C) was counted in the L5 ventral and dorsal roots of five mice of each genotype. Control mice were age matched with SOD1G85R mice with the same neurofilament content (NF-L +/+, 12 months; NF-L −/−, 13.5 months). Error bars are standard errors.
Figure 5
Figure 5
Peripherin neither compensates for absence of neurofilaments nor contributes significantly to selective vulnerability of motor neurons to SOD1G85R toxicity. (A) Levels of peripherin in sensory and motor axons determined by immunoblotting extracts (20 μg) of ventral or dorsal root tissue from 6-month-old NF-L −/− and NF-L +/+ mice. (B) Coomassie blue stain of a parallel gel.
Figure 6
Figure 6
Higher accumulated levels of NF-H subunits in motor neuron cell bodies in mice homozygously deleted for NF-L. Unphosphorylated NF-H was detected with antibody SMI-32 in motor neuron cell bodies in frozen spinal cord sections from normal mice (A) or mice homozygous for disruption of the NF-L gene (B). (Bar, 30 μm.)
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References

    1. Rosen D R, Siddique T, Patterson D, Figlewicz D A, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan J P, Deng H X, et al. Nature (London) 1993;362:59–62. - PubMed
    1. Deng H-X, Hentati A, Tainer J A, Iqbal Z, Cayabyab A, Hung W-Y, Getzoff E D, Hu P, Herzfeldt B, Roos R P, et al. Science. 1993;261:1047–1051. - PubMed
    1. Siddique, T. & Deng, H. X. (1996) Hum. Mol. Genet. 5, Suppl. 1465–1470. - PubMed
    1. Radunovic A, Leigh P N. J Neurol Neurosurg Psychiatry. 1996;61:565–572. - PMC - PubMed
    1. Fridovich I. Annu Rev Biochem. 1995;64:97–112. - PubMed

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