Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis.
We generated four transgenic mice with a 34 kb genomic fragment including the complete human neurofilament heavy (NF-H) gene. This human NF-H fragment contained all regulatory elements for tissue-specific expression, and in two transgenic lines, human NF-H proteins were produced at levels up to 2-fold the levels of endogenous mouse NF-H protein. By 3-4 months of age, these NF-H transgenics progressively develop neurological defects and abnormal neurofilamentous swellings that are highly reminiscent of those found in amyotrophic lateral sclerosis (ALS). We propose that a modest up-regulation of NF-H cross-linkers can result in an impairment of neurofilament transport, causing neuronal swellings with ensuing axonopathy and muscle atrophy, a mechanism of pathogenesis pertinent to the possible etiology of ALS.
Côté
F
F
Centre for Research in Neurosciences McGill University, Canada.
Collard
J F
JF
Julien
J P
JP
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009133:Muscular Atrophy / Q000378:metabolism; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology
D016900:Neurofilament Proteins; C051774:neurofilament protein H