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 neu rofilament 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 express ing, solely or concomitantly, the hNF-H and the human neurofilament light ( hNF-L) proteins. We report here that the motor neuron disease caused by exc ess hNF-H proteins can be rescued by overexpression of hNF-L in a dosage-de pendent fashion. In hNF-H transgenic mice, the additional hNF-L led to redu ction of perikaryal swellings, relief of axonal transport defect and restor ation of axonal radial growth. A gene delivery approach based on recombinan t adenoviruses bearing the hNF-L gene also demonstrated the possibility to reduce perikaryal swellings after their formation in adult mice. The findin g that extra NF-L can protect against NF-H-mediated pathogenesis is of pote ntial importance for ALS, particularly for cases with NF-H abnormalities.