title: Formation of intermediate filament protein aggregates with disparate effects in two transgenic mouse models lacking the neurofilament light subunit.
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.
authors.affiliation: Centre for Research in Neurosciences, McGill University, The Montreal General Hospital Research Institute, Montreal, Quebec, Canada H3G 1A4.
authors.forename: J M
authors.initials: JM
authors.lastname: Beaulieu
authors.forename: H
authors.initials: H
authors.lastname: Jacomy
authors.forename: J P
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002919:Chymotrypsinogen / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D018390:Gene Targeting; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007381:Intermediate Filament Proteins / Q000096:biosynthesis*; D008562:Membrane Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D017830:Octoxynol / Q000737:chemistry; D064531:Peripherins; D017434:Protein Structure, Tertiary
chemical_list: D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C578994:PRPH protein, human; D064531:Peripherins; C044882:neurofilament protein L; C051774:neurofilament protein H; D017830:Octoxynol; D002919:Chymotrypsinogen