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The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Mice engineered to express a transgene encoding a human Cu/Zn superoxide dismutase (SOD1)
with a Gly93 
Ala (G93A) mutation found in patients
who succumb to familial amyotrophic lateral sclerosis
(FALS) develop a rapidly progressive and fatal motor
neuron disease (MND) similar to amyotrophic lateral sclerosis (ALS). Hallmark ALS lesions such as fragmentation of the Golgi apparatus and neurofilament
(NF)-rich inclusions in surviving spinal cord motor neurons as well as the selective degeneration of this population of neurons were also observed in these animals. Since the mechanism whereby mutations in SOD1 lead
to MND remains enigmatic, we asked whether NF inclusions in motor neurons compromise axonal transport during the onset and progression of MND in a line
of mice that contained ~30% fewer copies of the transgene than the original G93A (). The
onset of MND was delayed in these mice compared to
the original G93A mice, but they developed the same
neuropathologic abnormalities seen in the original
G93A mice, albeit at a later time point with fewer vacuoles and more NF inclusions. Quantitative Western blot
analyses showed a progressive decrease in the level of
NF proteins in the L5 ventral roots of G93A mice and a
concomitant reduction in axon caliber with the onset of
motor weakness. By ~200 d, both fast and slow axonal
transports were impaired in the ventral roots of these
mice coincidental with the appearance of NF inclusions and vacuoles in the axons and perikarya of vulnerable
motor neurons. This is the first demonstration of impaired axonal transport in a mouse model of ALS, and
we infer that similar impairments occur in authentic
ALS. Based on the temporal correlation of these impairments with the onset of motor weakness and the
appearance of NF inclusions and vacuoles in vulnerable
motor neurons, the latter lesions may be the proximal
cause of motor neuron dysfunction and degeneration in
the G93A mice and in FALS patients with SOD1 mutations.
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