Extra neurofilament NF-L subunits rescue motor neuron disease caused by overexpression of the human NF-H gene in mice.
Previous studies demonstrated that transgenic mice overexpressing human neurofilament heavy (hNF-H) protein develop a progressive motor neuron disease characterized by the perikaryal accumulations of neurofilaments resembling those found in amyotrophic lateral sclerosis (ALS). To further investigate this neurofilament-induced pathology, we generated transgenic mice expressing, solely or concomitantly, the hNF-H and the human neurofilament light (hNF-L) proteins. We report here that the motor neuron disease caused by excess hNF-H proteins can be rescued by overexpression of hNF-L in a dosage-dependent fashion. In hNF-H transgenic mice, the additional hNF-L led to reduction of perikaryal swellings, relief of axonal transport defect and restoration of axonal radial growth. A gene delivery approach based on recombinant adenoviruses bearing the hNF-L gene also demonstrated the possibility to reduce perikaryal swellings after their formation in adult mice. The finding that extra NF-L can protect against NF-H-mediated pathogenesis is of potential importance for ALS, particularly for cases with NF-H abnormalities.
Meier
J
J
Centre for Research in Neuroscience, McGill University, The Montreal General Hospital Research Institute, Quebec, Canada.
Couillard-Després
S
S
Jacomy
H
H
Gravel
C
C
Julien
J P
JP
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001284:Atrophy; D001370:Axonal Transport; D001369:Axons / Q000473:pathology; D003599:Cytoskeleton / Q000473:pathology; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016900:Neurofilament Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism / Q000627:therapeutic use; D016879:Salvage Therapy
D016900:Neurofilament Proteins; D020033:Protein Isoforms; C044882:neurofilament protein L; C051774:neurofilament protein H