A team of researchers is proposing a new way of understanding Amyotrophic Lateral Sclerosis (ALS), the devastating and incurable neurological disease. This could be a major milestone on the path to a treatment for both ALS and dementia.
By delving into a previously overlooked corner of ALS research, Professor Peter St. George-Hyslop and his team from University of Toronto discovered a new way in which the disease kills nerve cells.
"These are dreadful diseases, the more we know about how they work, the faster we'll find treatments or even a cure," says St. George-Hyslop.
Many cases of ALS are sparked by a toxic build-up of certain proteins, which cause neurons in the brain and spinal cord to die. Paralysis and suffocation result, meaning that few people live more than five years with an ALS diagnosis. Over the last decade, mutations that cause ALS have been found in a growing number of genes that encode RNA-binding proteins. The protein they create commonly builds up inside the diseased brain and spinal cords in ALS patients. Until now, scientists haven't thought this build-up was important to the disease process because it looked different from the types of protein accumulations -- such as tau, amyloid and alpha synuclein -- that are clearly toxic and always found in patients with Alzheimer's, Parkinson's and some forms of dementia.
The FUS protein normally plays a key role in the healthy functioning of neurons, which transmit nerve signals in the brain and spinal cord. However, FUS and other proteins in its RNA-binding class seem to operate differently from many other cellular proteins.
The research team found that mutations in FUS changed the property of FUS protein so that it tends to form very dense gels that do not easily re-melt and release their cargo appropriately. As a result, it's unable to deliver the tools necessary for the neurons to stay healthy and do their job.
St. George-Hyslop noted that this kills the nerve by throttling it and preventing it from making new protein in the parts of the cell that desperately need it, adding the mutations force the gelling process to go further than it should have gone.
The next step is for researchers to find ways to prevent the solidification of the gel, or to reverse the hardening process, offering a key to a future drug to treat ALS and frontotemporal dementia -- another disease in which the protein is active.
The discovery has implications for other, more common forms of ALS that have accumulations of other over-gelled RNA binding proteins.
The study is published in the journal Neuron.
