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Oxidative
Stress, Mutant SOD1, and Neurofilament Pathology in Transgenic Mouse Models
of Human Motor Neuron Disease |
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Pang-hsien
Tu, Mark E. Gurney, Jean-Pierre Julien, Virginia M.-Y. Lee, and John Q.
Trojanowski |
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Department
of Pathology and Laboratory Medicine (PT, VM-YL, JQT), University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania; Central Nervous System Diseases
Research Unit (MEG), Upjohn Laboratories, Kalamazoo, Michigan; and Centre
for Research in Neuroscience (J-PJ), The Montreal General Hospital Research
Institute, Montreal, Canada |
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Amyotrophic lateral sclerosis
(ALS) is a neurodegenerative disease that primarily affects motor neurons
in the spinal cord and brain stem. About 10% of all ALS cases are familial
(FALS), inherited in an autosomal dominant manner. One fifth of FALS patients
carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several
lines of transgenic mice have been engineered to express mutant forms of
the SOD1 gene that are linked to FALS. Significantly, many of these transgenic
lines of mice develop a motor neuron disease (MND) that resembles human
FALS. Oxidative stress induced by human SOD1 mutations is believed to play
an important role in the pathogenesis of FALS and the FALS-like MND seen
in the mutant SOD1 transgenic mice. For example, two lines of these mice
showed prominent degeneration of mitochondria and endoplasmic reticulum
in spinal cord neurons. Furthermore, recent studies have shown that neurofilament
(NF)-rich spheroids, Lewy body\Nlike NF inclusions, altered ubiquitin immunoreactivity,
and Golgi fragmentation occur in the spinal cord motoneurons of these mutant
SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities
of human ALS, mutant SOD1 transgenic mice provide a useful model for studies
designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice
that overexpress NF proteins also develop a clinical and pathologic phenotype
similar to human MND, and polymorphisms in an NF gene have been linked to
patients with ALS. Collectively, these observations implicate NF protein
abnormalities in the pathogenesis of this disorder. Accordingly, this review
summarizes recent insights into mechanisms of motor neuron degeneration
in ALS that have emerged from studies of these new animal models of this
neurodegenerative disease. |
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