Identifying the early biochemical signature of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease, MND) 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. Accumulation of abnormal protein within affected nerve cells is a universal finding in people with ALS. ALS can affect anyone, but 10% of cases carry an alteration in the code of one of a handful of genes meaning that they are very likely to develop the disease. Although the symptoms of ALS can start at any time, they usually begin in middle age, even in people who have carried a disease-causing genetic alteration from birth. This tells us that there must be compensatory mechanisms that allow motor neurons to cope with such changes. By the time people with ALS are diagnosed, these compensatory mechanisms are exhausted and motor neurons have already suffered irreparable damage. Although targeted treatment for the genetic forms of ALS is currently being tested, the irreversible damage already established by diagnosis means that treatment is likely to remain difficult 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 to understand the early events that occur before damage occurs, the mechanisms that delay its onset and identify a signature of the disease before symptoms begin. Cerebrospinal fluid (CSF) is the closest fluid to the cells affected by ALS. It contains proteins and other substances produced by cells of the nervous system and is therefore the best place to look for change. Within CSF, tiny fluid-filled bubbles released by nervous system cells called extracellular vesicles (EVs) are found. They carry proteins that open a window on the internal mechanics of nervous system cells. In this study, samples of CSF and blood will be collected from gene carriers before the onset of ALS, as well as from healthy non-genetic carriers and patients who have already developed ALS. Repeated samples will be collected from individuals at yearly intervals, to allow monitoring of changes over time. This study will use proteomics - a state-of-the-art technique that allows the simultaneous measurement of thousands of proteins - to examine CSF and CSF EVs. Comparing the patterns of protein change in these different groups of people will reveal the compensatory pathways that occur before symptoms and shed light on the key events occurring before the onset of muscle weakness. The project will also study the role of these mechanisms in the disease by looking at cell models of the disease and examining nervous system and brain tissue of people who have died of ALS. This work will allow better prediction of the risk and timing of the development of ALS in genetically-susceptible individuals allowing earlier treatment, but also identify the key pathways driving the development of ALS in patients more widely to enable new treatment development, as well as developing markers for the monitoring of the effectiveness of potential therapies.