At any one time, there are about 20,000 Americans affected with ALS, also known as Lou Gehrig’s Disease. Patients with ALS often present with muscle weakness/cramping or slurred speech. Symptoms are progressive and debilitating, affecting a patient’s ability to move, speak, and, eventually breathe. Despite the many patients, there is little treatment available to combat the disease. Dr. Arthur Horwich, Professor of Genetics at Yale School of Medicine, hopes to understand the basic mechanisms in ALS that lead to motor neuron dysfunction and cell death, with a view to finding ways to develop drugs that could treat this lethal disease. His work is motivated by the people that such breakthroughs will save. So challenging is ALS that Tony Judt, a famous British/American historian of the 20th century who developed and succumbed to the disease, described it as “imprisonment without the chance of parole.” Dr. Horwich and his team are aiming to change that outcome.

Currently, the only drug available for patients with ALS is riluzole, which prolongs life by about 1-2 months. One approach Dr. Horwich and others have taken is to study mutant SOD1 transgenic mice, which develop ALS resembling the human disease; mutant forms of SOD1 cause about 20% of inherited ALS. Dr. Horwich finds that when these mice also express a “chaperone” protein called Hsp110, it appears to protect against motor neuron damage, and these animals survive much longer. Additionally, he and his team are carrying out electrophysiology studies, with Professor David McCormick at Yale, shedding light on the motor neurons that are most vulnerable in ALS; further studies of molecules involved may allow them to figure out how to protect these vulnerable neurons. He is also screening ALS mice that have been mutagenized, seeking to identify individuals that never get ALS; this will identify the genes that can carry out rescue. In this experiment, Dr. Horwich is taking a “black box” approach, looking for whatever system will lead to a solution that could completely alter the trajectory of disease of patients with ALS. In his own words, Dr. Horwich says, “It doesn’t matter which system leads to rescue; we have a chance to find it and go to the clinic.”

Current research includes:

• Improving Survival of the mutant SOD1 mice: Dr. Horwich and his team have identified a protein, called Hsp110, that may improve the survival of patients with ALS. The current experimental mouse model expresses the mutant SOD1 protein with an attached yellow fluorescent protein (YFP), so it is fluorescent within motor neurons. In the mutant ALS animals' spinal cord, Dr. Horwich can see the mutant fluorescent protein form large aggregates and has observed that this is associated with motor neuron cell death. He can also use the YFP "handle" to pull out chaperone proteins that associate with the mutant SOD1. Hsp110 was pulled out by such an approach, and studies of a number of groups indicate that the protein can function as a disaggregase, a potentially protective action to disarm the mutant SOD1 in their ALS mice.

• The “black box” mutagenesis approach looks blindly for mutant SOD1 mice that live indefinitely, never becoming affected by ALS, as the result of a random mutagenesis. The gene that is mutationally “hit” to effect rescue can be identified and will identify a pathway that is involved with rescue and lead to a drug approach.

• Mechanism of motor neuron and motor circuit dysfunction in ALS: ALS is a disease that attacks the motor neurons, and Dr. Horwich is trying to dig down to the basic mechanisms. He and his team have carried out never before accomplished electrophysiology studies with Professor McCormick on both the wild-type and ALS mutant SOD1 adult mice, preparing viable acute spinal cord slices. They have discovered that there are four basic firing types of motor neurons, and most revealing, the fastest firing motor neuron type dies in the mutant ALS mice by four months of age during a course to paralysis by six months of age. Understanding the molecular profile of this particular motor neuron population might provide a clue to why these cells die and may indicate how to protect them from death. In further electrophysiology studies, the group seeks to learn whether and how the motor system might “adapt” to losing the fastest firing neurons and, if so, whether such adaptation can be enhanced.