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

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Abstract
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.