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