Researchers at the University of Arizona have found an exciting treatment for Amyotrophic Lateral Sclerosis (ALS), also called Lou Gehrig’s disease. ALS is a progressive disease of the body’s motor neurons, resulting in the patient being unable to speak, eat, breathe, or move.
Patients with ALS and other degenerative neurological diseases have TDP-43 (TAR DNA-binding protein 43) and FUS gene aggregates, which can accumulate to lethal levels. Assistant professor of molecular and cellular biology, Ross Buchan, says “It's not clear yet if TDP-43 aggregates themselves are truly toxic or a sign that things have gotten in a cell, and this is its last Hail Mary trying to keep things in order. These aggregates could possibly be toxic because they are trapping other useful molecules and not letting them do their job.”
Buchan’s team of researchers began studying how healthy cells remove harmful aggregates, and they found two unexpected mechanisms at work. The first was that endocytosis was removing the aggregates already inside the cell. Normally, endocytosis is a cellular process that occurs when substances are brought inside a cell, rather than removed from the cell. Second, there is already a molecular process (autophagy) that is responsible for removing aggregates from cells. But in this case, endocytosis was doing the job normally done by autophagy.
Buchan explains, "If we genetically or chemically impede the pathway, then the TDP-43 protein accumulates and becomes super toxic. The cool thing, as far as a therapy for ALS is concerned, is that we can also do the reverse. We can make the endocytosis pathway work better by over-expressing parts of it, like putting the gas pedal down so it goes really fast. When we do that, then the TDP-43 aggregates are cleared really efficiently and it's no longer toxic."
This research is encouraging, and the next step for Buchan’s team is to figure out how TDP-43 and FUS enter the endocytic pathway and then improve the endocytosis in these cells.