Our Researchers

They collaborate; they share their toys; they’re creative; they’re psyched. The Center’s 31 scientists from labs across this country and Europe are handpicked for their expertise in specific aspects of the search for the cure. Here we highlight some of their work.

Don W. Cleveland, Ph.D.
University of California at San Diego
Finding Which Cells Are Directly Damaged by Familial ALS-linked SOD1 Mutants

Adding to his earlier find that ALS probably doesn’t start in motor neurons, Don Cleveland has continued his methodical examination of various central nervous system cells, seeking their possible role in the disease. This year, he focused on the small resident immune cells, microglia. In work on the most common ALS model—mice carrying a mutant human SOD1 gene—Cleveland effectively turned off the flawed gene only in the rodents’ microglia. Other nervous system cells still carried the mutant form. The fact that the animals lived three months longer than usual—significant time in the mouse lifespan—highlights the importance of microglia in the disease. It’s especially interesting, Cleveland says, because several ways already exist to quiet renegade microglia that might be applied as therapy.

Richard Ransohoff, M.D.
Lerner Research Institute,
Cleveland Clinic Foundation
The Role of Microglial CX3CR1 in the SOD1 Transgenic Mouse Model

Microglia, the central nervous system’s immune cells, have two faces: They defend against bacteria and viruses, yet their inflammatory properties give the potential to injure delicate neurons.

Richard Ransohoff previously discovered that neurons continuously secrete a potent agent called CX3CL1—one that damps down microglial inflammatory damage by acting directly on receptors on their cell membranes. Mice without microglial receptors or without the agent that quiets them risk dramatic death of their neurons and microglia.

Now Ransohoff has explored how microglia may act in ALS by using standard SOD1 model mice without the microglial receptors. They experience severe loss of spinal cord motor neurons; their lives are even shorter than typical SOD1 mice. Given the receptors’ importance, Ransohoff, a new grantee, hopes to uncover their mechanism. He suspects that receptors both quiet microglia and trigger protective processes in neighboring motor neurons.

Because existing anti-inflammatory drugs can affect microglial behavior, his research may rapidly translate to therapy.

Val Culotta, Ph.D.
Johns Hopkins University
The Impact of Glutathione and the CCS Copper Chaperone on Mutant Polypeptides of SOD1

Val Culotta’s science is the most basic of the basic. But this year’s work has brought light to the dimly understood chemistry of ALS, highlighting places things could go wrong. Using yeast and human cells as models, Culotta explores the chemical behavior of the molecular source of familial disease—the mutant SOD1 protein. Underlying her work is the idea that a gene mutation results in a poorly formed protein, which then unnaturally clumps in cells, helping trigger the downhill path. SOD1 in healthy people is extremely stable, Culotta’s found. The protein is unusual in that, to work properly and stay stable, it must acquire charged copper and zinc atoms. This year, Culotta has focused on how copper finds its way in. The traditional path has been known some time. But Culotta’s found a new route that cells use. More important, she’s shown that both that path and the better-known one are needed to keep frailer, mutant SOD1 from coming undone and clumping.

Why’s that important?

Culotta has long sought ways that environmental factors might alter cell chemistry and tip the balance toward disease. Though environmental triggers—if they exist—haven’t been found, she’s working in that direction. Finding potential pathways that can go awry is a key first step.

Jeffrey Johnson, Ph.D.
University of Wisconsin
The Role of Oxidative Stress in Initiation and Progression of ALS in SODG93A Mice

An exciting approach to therapy—one that strengthens a cell’s natural programs to overcome threats or damage—has begun to prove itself this year in ALS animal models. Work by Packard scientist Jeffrey Johnson centers on increasing a molecule, Nrf2, that acts as a key, of sorts, to open a cell’s built-in protective system against nerve cell insults. The molecule taps into all of a cell’s defense mechanisms simultaneously, helping to damp down harmful processes like excitotoxicity and the buildup of free radicals typical of ALS.

Earlier, Johnson showed Nrf2’s ability to limit damage to cell cultures exposed to neuron-killing toxins. This year, he’s shown that the molecule significantly delays motor neuron death, loss of strength and paralysis in SOD1 model mice. In the study, he injected the animals’ leg muscles with a safe virus carrying Nrf2 genes. The resulting Nrf2 protein triggered protective reactions that helped sustain the muscles—benefits that apparently carried over to neighboring motor neurons.

Elizabeth M.C. Fisher, Ph.D.
Institute of Neurology,
Queen Square, London
Why the Dynein Mutation Ameliorates the SOD1 ALS Phenotype and Considerably Extends Lifespan

For some time, Elizabeth Fisher and colleagues have worked with the “Legs at odd angles” (Loa) mouse, an animal with mild but progressive motor neuron disease. In 2001, they identified the responsible mutated gene; it forms a flawed version of the protein dynein needed for a neuron’s internal transport of materials. In this year’s study, in which she expected to see more intense motor neuron problems, Fisher crossed the Loa mouse with the classic familial ALS model, the SOD1 mouse. To her surprise, onset of symptoms in the offspring was considerably delayed. Further, the mice lived a third longer than the typical ALS model.

Fisher suspects there’s some unexpected but useful interaction between the Loa and the SOD1 mutations. She’s investigating the basic biology of the double mutant mice to shed light on ALS’s downhill path and new ways to treat it. Her work highlights axonal transport as a focus of ALS research.

Philip Wong, Ph.D.
Johns Hopkins University
Generation and Characterization of Wild-Type and Mutant Dynactin Transgenic Mice

Packard scientists have come to realize that a variety of animal models of ALS are needed to advance knowledge of the disease and hasten a cure. A case in point is the new mouse model of ALS that Philip Wong developed, one fairly different from the classic SOD1 model long in use. Wong’s model carries the recently discovered mutant gene for a familial neuromuscular disease with ALS-like characteristics. The animal’s illness more closely resembles ALS. Also, the model can confirm the importance of toxic pathways found in the SOD1 mouse. Finally, it brings a new tool for testing potential drugs, something missing in earlier models.

Kathryn Wagner, M.D., Ph.D.
Johns Hopkins University
Myostatin Inhibition for Motor Neuron Disease

Part of the body’s internal system of checks and balances involves a protein called myostatin. It’s a self-made molecule that puts a brake on muscle growth. Research in mice, cattle and humans has shown that in the absence of myostatin, muscle growth approximately doubles. So far, scientists studying muscular dystrophy have shown that the myostatin approach greatly helps animal models of the disease. This year, new Packard grantee Kathryn Wagner started work to see if blocking myostatin might have the same effect on muscles of ALS models and on motor neurons themselves. If the myostatin-lacking, mutant SOD1 mouse model of ALS she’s engineering does well, she’ll have an answer.