Formation of intermediate filament protein aggregates with disparate effects in two transgenic mouse models lacking the neurofilament light subunit

Protein aggregates containing intermediate filaments (IFs) are a hallmark o f 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 inclusi ons with ensuing motor neuron death in transgenic mice overproducing periph erin, 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 inclusio ns, we generated transgenic mice overexpressing human neurofilament heavy s ubunits (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 develope d 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 a ggregates with distinct properties may occur in a context of NF-L deficienc y and that an axonal localization of such aggregates may be an important fa ctor of toxicity.