Wobbler Mouse Gene ID May Unlock New Doors

A mutation in a gene for the vps54 protein, which acts as a cellular traffic manager, leads to the abnormal gait and reduced strength that characterize a much-studied mouse with a neurologic disease, says a U.S., Danish and German research team.

The mouse, known as wobbler, was first identified at the University of Edinburgh (Scotland) in 1956. Before mouse models of amyotrophic lateral sclerosis (ALS) based on mutated SOD1 genes were developed in the mid-1990s, the wobbler was a popular method of simulating an ALS environment in which to test treatments.

For the last decade, SOD1 mutant mice have held center stage in ALS research, but not everyone is convinced they’re the only, or the best, models for all forms of ALS. (Only about 2 percent of ALS patients have mutations in an SOD1 gene.)

Thomas Schmitt-John at the University of Aarhus in Denmark and colleagues, who published their gene identification in the November issue of Nature Genetics, say they’ll now develop mice missing vps54 and study its disruption in cells in lab dishes.

“I think that the SOD1 mice are surely good animal models for the familial ALS cases associated with SOD1,” Schmitt-John said. “But ALS is a disease with a variety of molecular causes, and the precise mechanism leading to the death of the neurons [nerve cells] might differ dramatically [in each]. So I think that more animal models are required.”

Walter Bradley, who directs the Kessenich Family MDA/ALS Center at the University of Miami, and Hiroshi Mitsumoto, who co-directs the Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University in New York, have worked with the wobbler mouse intermittently for several decades.

Bradley, who says the wobbler mouse shows evidence of impaired transport along its motor neuron axons (long fibers), has speculated that vps54 is involved in loading material onto a transport system. It’s one of several vesicular protein sorters that assign compounds to bubbles, or vesicles, for shipment to other parts of the cell.

Substances can move from one cell compartment to another via vesicles that bud off from one compartment, move along a cellular conveyor belt called a microtubule, and then fuse with another compartment.

Schmitt-John says the vps54 finding indicates to him that “vesicle trafficking should be considered as a critical factor in ALS pathology.”