Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by motoneuron degeneration and muscle paralysis. Although the precise pathogenesis of ALS remains unclear, mutations in Cu/Zn superoxide dismutase (SOD1) account for ∼20–25% of familial ALS cases, and transgenic mice overexpressing human mutant SOD1 develop an ALS-like phenotype. Evidence suggests that defects in axonal transport play an important role in neurodegeneration. In Legs at odd angles (Loa) mice, mutations in the motor protein dynein are associated with axonal transport defects and motoneuron degeneration. Here, we show that retrograde axonal transport defects are already present in motoneurons of SOD1G93A mice during embryonic development. Surprisingly, crossing SOD1G93A mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1G93A mice. Moreover, there is a complete recovery in axonal transport deficits in motoneurons of these mice, which may be responsible for the amelioration of disease. We propose that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS.

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Tetanus toxin binds specifically to motor neurons at the neuromuscular junction. There, it is internalized into vesicular carriers undergoing fast retrograde transport to the spinal cord. Despite the importance of this axonal transport pathway in health and disease, its molecular and biophysical characterization is presently lacking. We sought to fill this gap by determining the pH regulation of this compartment in living motor neurons using a chimera of the tetanus toxin binding fragment (

Poliovirus (PV), when injected intramuscularly into the calf, is incorporated into the sciatic nerve and causes an initial paralysis of the inoculated limb in transgenic (Tg) mice carrying the human PV receptor (hPVR/ CD155) gene. We have previously demonstrated that a fast retrograde axonal transport process is required for PV dissemination through the sciatic nerves of hPVR-Tg mice and that intramuscularly inoculated PV causes paralytic disease in an hPVR-dependent manner. Here we showed that hPVR-independent axonal transport of PV was observed in hPVR-Tg and non-Tg mice, indicating that several different pathways for PV axonal transport exist in these mice. Using primary motor neurons (MNs) isolated from these mice or rats, we demonstrated that the axonal transport of PV requires several kinetically different motor machineries and that fast transport relies on a system involving cytoplasmic dynein. Unexpectedly, the hPVR-independent axonal transport of PV was not observed in cultured MNs. Thus, PV transport machineries in cultured MNs and in vivo differ in their hPVR requirements. These results suggest that the axonal trafficking of PV is carried out by several distinct pathways and that MNs in culture and in the sciatic nerve in situ are intrinsically different in the uptake and axonal transport of PV.In humans, paralytic poliomyelitis results from the invasion of the central nervous system by circulating poliovirus (PV), probably via the blood-brain barrier. This conclusion is supported by the finding that circulating PV after intravenous inoculation in mice appears to cross the blood-brain barrier at a high rate in a human PV receptor (hPVR/CD155)-independent manner (44). After the virus enters the central nervous system, it replicates in neurons, especially in motor neurons (MNs), inducing the cell death that causes paralytic poliomyelitis. Along with this route of dissemination, a neuron-specific pathway has been reported in humans (31), monkeys (18), and PV-sensitive transgenic (Tg) mice carrying the hPVR gene (34,37). This neuron-specific pathway appears to be important in causing "provocation poliomyelitis," which is triggered by injuries after PV ingestion (11). Using differentiated PC12 cells and a PV-sensitive Tg mouse line, we have shown that intramuscularly inoculated PV is taken up by endocytosis at synapses.hPVR is a member of the immunoglobulin (Ig) superfamily, with three linked extracellular Ig-like domains, followed by a membrane-spanning domain and a cytoplasmic domain. Two membrane-bound forms (␣ and ␦) and two secreted forms (␤ and ␥) of hPVR derived by alternative splicing are likely to be expressed in human cells (23). Membrane-bound hPVRs are considered to play important roles in the early steps of infection, such as the binding of the virus to the cell surface, its entry into the cell, and the uncoating of the virus. The N-terminal Ig-like domain harbors the sites for PV binding, and antihPVR monoclonal antibodies (MAbs) directed against this region block PV infection (9,24,39).hPVR ...

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is the Chief Technology Officer for UVP, Inc., an instrumentation and specialty light source company that manufactures and distributes a broad spectrum of innovative instrument and imaging system solutions for the academic, clinical, medical and industrial laboratory. In his role as CTO, Sean oversees technical operations of UVP, including research, product and applications development, engineering, and technical support. Prior to UVP, Sean held leadership roles in instrumentation, fluidic packaging, and applications development with Hoefer Scientific Instruments, Pharmacia Biotech and Motorola Labs, where he established the microfluidcs laboratory and was a founding director of Motorola Life Sciences.