Mar. 12 2015
Molecular detective work unlocks the mysteries of ALS

Last summer saw the likes of Matt Damon and Bill Gates douse themselves in buckets of ice water as part of wildly successful viral campaign for amyotrophic lateral sclerosis, or ALS, an incurable disease that progressively disables nerve cells that control voluntary muscle movement.

The Mailman School community has long been cognizant of the devastation ALS, which took the life of longtime dean Allan Rosenfield in 2008. Today, Diane Re, a new recruit to Environmental Health Sciences, is charting a course to an ALS cure by exploring toxic triggers for the disease within the brain and in our natural environment.

A native of Marseille, France, Re has been studying ALS for more than a decade. In 2005, she crossed the Atlantic to join the lab of Columbia neuroscientist Serge Przedborski. In a series of studies, the two researchers took conventional wisdom about the disease and flipped it on its head.

For many years, scientists believed that ALS happened because something had gone wrong in motor neurons—cells that control muscle movement. Re and Przedborski presented evidence painting a different picture: motor neurons were victims of their environment. Astrocytes, a common helper cell that outnumber and surround neurons in the brain and spinal cord, were killing off motor neurons in ALS patients. Since the discovery, Re has performed molecular sleuthing to understand how the astrocytes do their dirty work. In a forthcoming paper, she will reveal the specific poison—a toxic protein—that the ill-intentioned astrocytes use.

The implications could be huge.

“In the future, we might be able to recreate the conditions in the brain and spinal cord of ALS patients so that motor neurons can flourish, not wither and die,” Re says. One method would engineer motor neurons in ALS patients to be resistant to the astrocyte’s toxin. Another option would pacify astrocytes. Either way, with a healthy environment, doctors could potentially replace patients’ diseased motor neurons with healthy counterparts.

Green Algae and Heavy Metal

Since joining the Mailman School, first as the winner of a Career Development  Award and now as an assistant professor, Diane Re has focused on a very different environmental milieu: toxins in the natural environment. Only one in ten ALS cases has  a familial history, she emphasizes.  “Beyond rare inherited genetic mutations, we have to find what in the environment causes ALS.”

A prime suspect is a kind of green algae called cyanobacteria. As early as the 1960s, scientists hypothesized that a neurotoxin called BMAA released by the algae was behind a cluster of ALS-like illness in Guam. More recently, BMAA was discovered to make its way up the food chain, accumulating in crabs, sharks, and other marine life that people eat.

Re wonders whether BMAA is behind ALS clusters in Wisconsin, northern New England, and Florida. Her plan is to compare levels of the neurotoxin in brain tissue taken from ALS patients who lived in these areas with brain tissue from a control region. Future studies will look at how BMAA interacts with human tissue, and whether some people are immune to the toxin.

Meanwhile Re just obtained a Pilot Project Grant from the National Institute of Environmental Health Sciences Center of Nothern Manhattan for her working with Environmental Health Sciences chair Tomas Guilarte. This study will explore another possible environmental trigger, the industrial metal manganese. One enticing clue: the poison Re identified in ALS patients’ astrocytes is also present in animals exposed to manganese. Another project funded through the Department of Defense in collaboration with Guilarte will focus on a specific molecular outcropping, or ligand, on a cellular energy pipeline known as translocator protein TSPO. Using a tissue culture, Re showed that this ligand can shield ALS motor-neurons from the killer astrocytes. Next, she hopes to replicate the experiment in mice engineered to have ALS.

“If that works it will be very exciting because this molecule is already approved for use in human brains,” she explains. A viable therapy could be developed without worry that it would be toxic to patients, a major hurdle for any potential treatment.

Surprisingly, given the intensity and scope of her ALS research, Diane Re so far hasn’t been invited to take part in the Ice Bucket Challenge. “I’m up for it,” she says, “but I’d ask any would-be challengers to hold off until the weather warms up.”