Reduction of axonal caliber does not alleviate motor neuron disease caused by mutant superoxide dismutase 1

Abstract

It is well established that motor neurons with large axon caliber are selectively affected in amyotrophic lateral sclerosis (ALS). To investigate whether high neurofilament (NF) content and large axonal caliber are factors that predispose motor neurons to selective degeneration in ALS, we generated mice expressing a mutant form of superoxide dismutase 1 (SOD1 G37R ) linked to familial ALS in a context of one allele for each NF gene being disrupted. A Ϸ40% decrease of NF protein content detected in triple heterozygous knockout mice shifted the calibers of large axons in L5 ventral root from 5-9 m to 1-5 m, altering neither the normal subunit stoichiometry and morphological distribution of NFs nor levels of other cytoskeletal proteins. This considerable reduction in NF burden and caliber of axons did not extend the life span of SOD1 G37R mice nor did it alleviate the loss of motor axons. Moreover, increasing the density of NFs in axons by overexpressing a NF-L transgene did not accelerate disease in SOD1 G37R mice. These results do not support the current view that high NF content and large caliber of axons may account for the selective vulnerability of motor neurons in ALS caused by mutant SOD1.amyotrophic lateral sclerosis ͉ Cu͞Zn superoxide dismutase ͉ neurofilaments ͉ transgenic mice ͉ knockout mice

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

“…3B) or NeuN staining patterns of the spinal cord sections were similar between the HB9:Cre-Tardbp lx/Ϫ and control mice. Notably, consistent with the report that larger ␣ motor neurons in ALS were more vulnerable to degeneration (48), the % of reduction of the ␣ motor neurons (ϳ46%) in the 20-week-old HB9:Cre-Tardbp lx/Ϫ mice was larger than that of the ␥ motor neurons (ϳ25%), as estimated with use of the molecular markers (Fig. 4, lower panel).…”

Exacerbation of Motor Neuron Disease by Chronic Stimulation of Innate Immunity in a Mouse Model of Amyotrophic Lateral Sclerosis

“…The inbred C57BL/6 SOD1 G37R mice (line 29) used in this study have a life span of 10 -12 months (Nguyen et al, 2000). C57BL/6 SOD1 G37R mice (line 42) exhibit a life span of 5-6 months (Wong et al, 1995).…”

“…Figure 2 A shows the survival curve of SOD1 G37R mice (line 29) treated chronically with Veh or LPS. The SOD1 G37R mice treated with vehicle (n ϭ 16) used as control exhibited an average life span of 49.4 Ϯ 2.7 weeks and a median life probability of 49.0 weeks, which is not different from the life span of the nontreated SOD1 G37R mice (Nguyen et al, 2000(Nguyen et al, , 2001a. The median life probability is defined as the age at which the probability of survival is 50%.…”

Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1

“…The inbred C57BL6 SOD1 G37R mice (line 29) used in this study have a life span of 11-12 months (Nguyen et al, 2000(Nguyen et al, , 2001a. SOD1 G37R mice (line 29) overexpressing human neurofilament H (NF-H) were generated according to the methods of Nguyen et al (2001a) and exhibit a life span of 13-18 months (Couillard-Després et al, 1998, Nguyen et al, 2001a.…”