ALS is a devastating disease in which motor neurons - nerve cells that control voluntary movement - die prematurely, leading to progressive muscle weakness. In most cases, death occurs within three years from the onset of symptoms. There is currently no effective treatment.
ALS can affect anyone. Everyone with the disease has an accumulation of abnormal protein within affected nerve cells. But 10 per cent of people with ALS carry an alteration in the code of one of a handful of genes, meaning that these people are very likely to develop the disease. Although symptoms can start at any time, they usually begin in middle age, even in people who have carried a disease-causing genetic alteration from birth. So there must be compensatory mechanisms that initially allow motor neurons to cope with the build-up of abnormal protein.
I’m excited to begin working on this major project. By studying healthy people carrying genetic alterations that predispose them to motor neuron disease, I hope to shed light on the events that cause the disease and eventually enable treatment before symptoms begin.
- Alexander Thompson
By the time people with ALS are diagnosed, these compensatory mechanisms are exhausted and motor neurons have already suffered irreparable damage. Targeted treatment for the genetic forms of ALS is currently being tested. But the damage already done by the time of diagnosis means that treatment is likely to remain challenging unless we can identify signals of the disease before symptoms start.
Studying the cellular protein management processes in people carrying gene mutations before they have developed symptoms offers a unique opportunity. It will help scientists to understand the early events that occur before ALS begins, and the mechanisms that delay its onset. The aim is to identify a signature of the disease before symptoms begin.
In this project, Alex will examine cerebrospinal fluid (CSF), blood, and post-mortem brain cells and tissue. CSF contains proteins and other substances produced by cells of the nervous system and is therefore the best place to look for change in the cells affected by ALS. Within CSF, tiny fluid-filled bubbles released by nervous system cells called extracellular vesicles (EVs) are found. They carry proteins that shed light on the internal mechanics of nervous system cells.
Alex and colleagues will collect samples of CSF and blood over time from three groups: people who carry the known genes before the onset of ALS; healthy people; and patients who have already developed ALS. The team will use proteomics, a state-of-the-art technique that allows us to measure thousands of proteins at the same time. Comparing the patterns of protein change in these different groups of people will reveal the compensatory mechanisms that operate before symptoms eventually occur, and shed light on what happens before the onset of muscle weakness.
This work will help to predict the risk and timing of developing ALS in genetically susceptible individuals. This will not only allow earlier treatment for this group, but will also identify the key drivers of the development of ALS in patients more widely. It will pave the way for developing new treatments, as well as new markers for monitoring their effectiveness.