The power of mouse genetics provides Susan Ackerman a whole new view of the mechanisms behind neurodegeneration.

With its rough, matted fur and pint-sized frame, the mouse strain known as "sticky" was destined for genetic study. Thus, a colony with the stimutation, which spontaneously arose in a university of Cambridge lab around 1984, was transferred to The Jackson Laboratory in Maine, to produce a line for dermatologic research.

There, a sharp-eyed research assistant noticed that, over time, the sticky strain developed additional, more disturbing traits: Starting with mild tremors in their limbs, the animals began losing muscle control, ultimately having difficulty walking or even moving.

Studies later showed that the aging mice gradually lost Purkinje cells in the cerebellar cortex, the part of the brain responsible for motor control and balance. That's when HHMI investigator Susan L. Ackerman entered the picture.

A geneticist at The Jackson Laboratory, Ackerman uses a "forward genetics" approach, starting with an organism's outward physical traits—or phenotype—and working back to identify the mutated gene. "Even as an undergraduate,I loved the idea of having a mutation in a gene that causes some sort of phenotype, and then trying to fill in the gaps between A and Z," she says. This strategy served her well in 1997, when she linked defects in developing brains to a gene critical to cell migration and axonal guidance. In 2002, her study of a mutant mouse called harlequin surprised the scientific community by revealing that a gene long thought to play a critical role in promoting neuron death actually functioned to keep nerve cells alive.

Photo: Paul Fetters

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