Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase

Abstract

To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1 G37R ) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1 G37R mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1 G37R alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1 G37R ;NF-Htransgenic littermates.

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

“…Our analysis of SOD1 G37R mice overexpressing human NF-H proteins is also consistent with a model in which Cdk5 precedes Cdk4 in the signaling pathway to neuronal death, as depicted in Figure 8. Previously, we showed that the overexpression of NF-H confers remarkable protection and delays the mortality of SOD1 G37R mice (Couillard-Després et al, 1998). The excess perikaryal NF-H can alleviate disease by acting as a phosphorylation sink for deregulated Cdk5 activity, thereby reducing hyperphosphorylation of other detrimental substrates such as tau (Nguyen et al, 2001a).…”

“…Our previous studies provided evidence that perikaryal neurofilament accumulations induced by overexpression of an hNF-H transgene can slow down disease in SOD1 G37R mice by acting as a phosphorylation sink for deregulated Cdk5 activity by p25, a toxic calpain-p35 truncated product (Couillard-Després et al, 1998;Patrick et al, 1999;Nguyen et al, 2001a). To further assess the effects of Cdk5 interference on Cdk4 levels, we analyzed by immunohistochemistry and Western blotting the expression of Cdk4 as well as phosphorylation of Rb in SOD1 G37R mice overexpressing hNF-H.…”

“…Cdk5, decreases the levels of nuclear Cdk4, attenuates Rb phosphorylation, and alleviates disease in SOD1 G37R mice To further assess the relationship between Cdk5 and Cdk4 in neurodegeneration, we analyzed SOD1 G37R mice overexpressing the human NF-H protein (hNF-H) (Couillard-Després et al, 1998;Nguyen et al, 2001a). Our previous studies provided evidence that perikaryal neurofilament accumulations induced by overexpression of an hNF-H transgene can slow down disease in SOD1 G37R mice by acting as a phosphorylation sink for deregulated Cdk5 activity by p25, a toxic calpain-p35 truncated product (Couillard-Després et al, 1998;Patrick et al, 1999;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. Treatment of SOD1 G37R mice (line 29) with minocycline was performed according to the methods of Kriz et al (2002).…”

Geração de espécies reativas de oxigênio e neuroinflamação induzidas por enucleação ocular no sistema visual de ratos.

“…Contudo, em animais knockouts para NF68 a regeneração de axônios mielinizados foi significativamente reduzida após axotomia, demonstrando que NFs contribuem para a regeneração das fibras nervosas após lesões. Além disso, o aumento da expressão de NF200 elevou em 65% a expectativa de vida de camundongos transgênicos para a SOD (COUILLARD-DESPRES et al, 1998). Desta maneira, o aumento da expressão de NFs tem sido constantemente associado a efeitos neuroprotetores.…”