Enzymes that unlock stress granules, our cells’ biological ‘storm shelters,’ open pathway to treating muscle, brain disorders
Discovery that the molecular switches ULK1/2 regulate disassembly of cell structures called stress granules raises the prospect of drugs to treat inclusion body myopathy, amyotrophic lateral sclerosis and frontotemporal dementia.
Our lab recently discovered that enzymes called ULK1 and ULK2 play a key role in triggering the disassembly of cell structures called stress granules. These structures form when the cell suffers such stresses as heating, toxic chemicals or pathogens. The stress granules are believed to be like biological “storm shelters” that temporarily protect genetic messenger RNA and proteins until the stress is removed.
What does this mean? The finding is important because stress granules that abnormally resist disassembly in certain muscle and brain disorders cause buildup of proteins that kill muscle and brain cells. This results in disorders like inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Our findings were recently published online in the journal Molecular Cell.
IBM causes weakness in arm and leg muscles. ALS, also known as Lou Gehrig’s disease, causes paralysis due to the death of nerve cells controlling voluntary muscles. FTD is a form of dementia that damages areas of the brain associated with personality, behavior and language.
We knew that the two nearly identical enzymes, ULK1 and ULK2, were important regulators of the cell process called autophagy—a mechanism by which the cell disassembles dysfunctional or unneeded proteins and other molecules. We also knew that defects in autophagy had been implicated in IBM, ALS and FTD.
So, this understanding gave us a good reason to explore in more detail how ULK1/2 played a role in these disorders.
Using preclinical models genetically engineered to have deficient activity of ULK1/2, we found muscle abnormalities resembling IBM in humans. Further experiments showed the abnormalities could not be attributed to a defect in autophagy alone.
Another surprise came when we screened for proteins that interacted with ULK1/2—identifying proteins associated with stress granules. And in the most important surprise, our experiments revealed ULK1/2 was a key switch in activating a protein called VCP. This finding was important, because VCP is known to be damaged by mutations in patients with IBM, ALS and FTD. These mutations prevent the normal disassembly of stress granules, leading to toxic buildup of cell-killing molecules.
The treatment potential of the discovery came when we found drugs called agonists that activate ULK1/2 accelerated the disassembly of stress granules. The drugs worked even in cells with disease-causing mutations.
I believe our studies raise the possibility that ULK agonists may be a way to disassemble persistent stress granules that are thought to contribute to these diseases.
We believe the mechanism we have discovered is particularly promising because, although VCP affects many different processes in the cell, this may be a way to selectively regulate VCP function. And, since ULK1/2 also regulates autophagy, boosting its function is also potentially a way to eliminate toxic proteins such as those that aggregate in patients with IBM. But first, we need to know much more about the mechanism of these processes.
Our lab plans further studies to explore in greater depth the effect of over-activating ULK1/2 in models of IBM, ALS and FTD. In addition, we’ll also look at the details of how ULK1/2 switches on VCP, to gain greater insight into how drugs might control that switching.