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“While we were busy trying to understand the mechanism of chaperones,” Horwich says, “a whole industrious group of people was learning that many common neurodegenerative diseases are associated with protein misfolding and aggregation. It was shocking to see that a number of these aggregates are occurring in the cytosol—the cell’s watery interior—where there should be a good supply of chaperones.”
In ALS, the aggregates form almost exclusively in the spindly motor neurons that extend down the body’s limbs and operate the muscles. Despite years of study, no one knows why this happens or whether the aggregates are a cause or a symptom of the disease. Tackling those questions requires the kind of experimental openness Horwich is known for. “We just have to look at it at all levels,” he says. “Electron microscopy, light microscopy, whole animal, embryonic stem cells if they’ll work, genomics.”
On a given day, you might find Fenton bent over a microscope, his long white beard dangling as he examines fledgling motor neurons cultured from stem cells. In the next room, postdoctoral researcher Urmi Bandyopadhyay might be examining a spinal cord cross-section from a mouse in the last stages of the murine equivalent of ALS. She guides a fine laser to cut out and capture, for further study, the protein clumps associated with the disease.
Making the Rounds
If it’s early in the morning, Horwich can be found in the basement of the building next door, making his daily rounds.
Most ALS cases in people are sporadic, meaning that the family of the affected person has no history of the disease. But roughly 10 percent of cases are familial, inherited from one generation to the next. Scientists have identified a number of genes associated with familial forms of ALS, and Horwich has homed in on one of them, called SOD1, to study a mouse model for the disease. He begins every day by checking in on his colony, many members of which have been bred to express mutations in SOD1.
The SOD1 gene codes for an abundant protein—it accounts for roughly 1 percent of the proteins in a cell’s cytosol—whose precise role in ALS is unknown. Horwich bred mice with a mutant form of the SOD1 protein, called G85R, that cannot fold properly and causes features of disease like those associated with ALS in humans, including partial paralysis and clumped proteins inside motor neurons. The mutation appears to cause a gain of function, not the loss of one: delete the gene entirely, and the animals survive.
How an animal could survive without a protein normally so abundant is one of the many questions in the overall ALS puzzle that Horwich’s lab is pursuing. Pinpointing the function gained as a result of the mutation associated with the disease is another. With Lifton, Horwich is also sequencing the protein-coding portions of genomes of ALS patients. In doing so, the scientists hope to explain the role of genetics in sporadic forms of the disease.