In the search for the underlying mechanisms of ALS, researchers are examining the role of even the tiniest parts of neuron cells.
In fact, studies have shown that in ALS patients, microtubules—which are the major component of the cell cytoskeleton and serve as tracks for transporting components from cell bodies to neuronal terminals—become dysfunctional.
But just how these microtubules are affected by ALS remained a mystery until research at the Les Turner ALS Center at Northwestern Medicine revealed the cause.
Vladimir Gelfand, the Leslie B. Arey Professor of Cell, Molecular, and Anatomical Sciences at Northwestern Medicine and an expert in studying cell cytoskeletons, analyzes the biochemistry and dynamics of the cytoskeleton in his Northwestern lab.
Using the well-studied fruit fly as a model to study genetic mutations—which works especially well when studying ALS, since many of the proteins involved in the disease are common to both fruit flies and humans—Gelfand turned his attention to microtubules in ALS.
“Microtubules are very important in the body,” he said. “So, everything that regulates microtubules in the body is important to us in the lab. A neuron’s life depends on microtubules and the molecular motor proteins that walk along them, so we decided to look at why they might be changed in ALS.”
In research funded by the Les Turner ALS Foundation, Gelfand and his graduate student Sun Kim found that a genetic mutation in the protein Ataxin-2 (ATXN2) disrupts the stability of microtubules, leading to impaired neuron growth and function.
Scientists had already known that ATXN2 was considered a genetic risk for ALS, but Gelfand and his team observed fruit flies with and without ATXN2 to determine the protein’s biological mechanism.
“We found that the dynamics of microtubules are dramatically changed when you mutate the gene encoding Ataxin-2,” Gelfand said.
Importantly, the team could restore normal microtubule function in fruit flies by giving them the human version of normal ATXN2. That suggests that this protein works similarly across species.
While this research still needs to be repeated in mammalian animal models, it does indicate that ALS could potentially be treated with therapies that are known to affect microtubules. Dozens of such drugs are already on the market, including those used to treat cancer.
Robert Kalb, director of the Les Turner ALS Center at Northwestern Medicine, said the convergence of microtubules and ATXN2 was “unexpected and an important step forward in our understanding.”
“Decades old research from Don Cleveland’s lab identified corruption of microtubule structure and function in ALS,” he said. “The current work from the Gelfand lab links a gene known to participate in disease progression (ataxin-2) with microtubule biology. Excitingly, the ataxin-2/microtubule nexus may be amenable to small molecule targeting and thus could be directly relevant to human therapeutics.”
Gelfand credits his grant from the Les Turner ALS Foundation as key to the breakthrough. “It’s a short-term grant that is a good starting point for developing new research,” he said. “You can start quickly and also get results very soon.”
Next, the team plans to study another protein that appears to affect microtubule dynamics called FEZ1.
“We know that without this protein, fruit flies die, so it is very important,” Gelfand said. “If it also affects microtubules, like we suspect, it could be another way to understand ALS.”
