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The Journal of Neuroscience, July 15, 2000, 20(14):5321-5328

Formation of Intermediate Filament Protein Aggregates with Disparate Effects in Two Transgenic Mouse Models Lacking the Neurofilament Light Subunit

Jean-Martin Beaulieu, Hélène Jacomy, and Jean-Pierre Julien

Centre for Research in Neurosciences, McGill University, The Montreal General Hospital Research Institute, Montreal, Quebec, Canada H3G 1A4

Protein aggregates containing intermediate filaments (IFs) are a hallmark of degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS). Recently, we reported that a deficiency in neurofilament light subunit (NF-L), a phenomenon associated with ALS, promoted the formation of IF inclusions with ensuing motor neuron death in transgenic mice overproducing peripherin, a type III IF protein detected in axonal inclusions of ALS patients. To further assess the role of NF-L in the formation of abnormal IF inclusions, we generated transgenic mice overexpressing human neurofilament heavy subunits (hNF-H) in a context of targeted disruption of the NF-L gene (hH;L/ mice). The hH;L/ mice exhibited motor dysfunction, and they developed nonfilamentous protein aggregates containing NF-H and peripherin proteins in the perikarya of spinal motor neurons. However, the perikaryal protein aggregates in the hH;L/ mice did not provoke motor neuron death, unlike toxic IF inclusions induced by peripherin overexpression in NF-L null mice (Per;L/ mice). Our results indicate that different types of IF protein aggregates with distinct properties may occur in a context of NF-L deficiency and that an axonal localization of such aggregates may be an important factor of toxicity.

Key words: neurofilament; peripherin; intermediate filament; transgenic mouse; ALS; amyotrophic lateral sclerosis; motor neuron disease; neurodegeneration

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20145321-08$05.00/0

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