Multiple System Atrophy (MSA) is a rare brain disorder that until recently was largely ignored by the research community. MSA is a rapidly progressing neurodegenerative disease caused by a decline of the body’s most basic and vital functions including breathing, digestion, urination, controlling blood pressure and movement. It is not known how MSA arises, and no environmental or genetic contributors have been identified. Several mechanisms are believed to contribute to the disease process. Brain inflammation, metabolic failure and protein accumulation are just some of the most important disease mechanisms and targeting all of these underlying features might be required to stop MSA from progressing. No disease-modifying drug currently exists for MSA and treatments are purely symptomatic.
Over the last two decades, interest in MSA research has increased within the academic and biopharmaceutical fields, which can be attributed to several reasons. In the late nineties, clumps of a protein called ‘alpha-synuclein’ were discovered inside brain cells. Alpha-synuclein was discovered to be a disease hallmark and a key brain lesion in people with MSA. After this discovery research into MSA accelerated (Fig. 1). A second catalyst appeared ten years later, when a new research hypothesis emerged. This research hypothesis, which initially sprang from other degenerative brain research, involving Parkinson and Alzheimer disease, was coined the “prion-like” hypothesis and showed striking similarities with how MSA might occur.
Figure 1. Representation of MSA-related research papers since the first English description of MSA. Graph indicates the number of published MSA papers per year on PubMed from 1962 until 2018.
The prion-like hypothesis raises a new and revolutionary idea in the neurodegenerative sciences. It examines the question of whether a protein can acquire a different shape that can cause disease to spread from one cell to the next – or one brain region to another. A slow and progressive but also vicious cycle then occurs where incorrectly folded proteins spread throughout the central nervous system causing cell loss along its path. This spread usually follows a disease-specific pattern because these sticky, abnormal proteins will disseminate along a path that is laid out between vulnerable connections, guided by inflammatory and metabolic cues, within the central nervous system. As a result, different areas within the nervous system become progressively affected, resulting in the typical symptoms that sequentially develop in MSA.
It can be hard to imagine how a protein misfolds, becomes sticky, starts to clump and cause cell damage because this is indeed quite abstract. There are over 50,000 different proteins in our body, 30,000 of which are present in our brain. Each of those proteins have their own task, and in order for us to be healthy, all of them have to properly and meticulously perform their task. In fact, forcing proteins to become sticky is something we do on a daily basis, for instance when we’re cooking. When boiling an egg, soluble proteins are turned insoluble, or sticky. During a five-minute boiling process, all of the liquid, soluble proteins in the egg form strong almost irreversible chemical bonds with other proteins, resulting in a large solid mass of clumped, sticky protein. As a result, you get a hard-boiled egg.
Intriguingly, some of the 30,000 proteins in our brain exist at concentrations that are so high that they have a natural tendency to stick together. Our brain has multiple natural defense mechanisms that prevent this clumping from happening. However, during aging, natural lines of defense become impaired, the immune system weakens, metabolic deficits arise, and that, along with other reasons we do not fully understand, allow some of these proteins to start clumping and disrupt the communication between cells.
Research into MSA has been very challenging, but the reason that sticky proteins have been so fascinating is that because out of 30,000 the proteins in our brain, one sticks out: alpha-synuclein. Clumps of alpha-synuclein, are invariably found inside sick cells of the brain, the spinal cord and certain specialized cells that directly connect the central nervous system with different organs, such as the intestines, heart, lungs, or the urinary system. It is thought that these sticky proteins can physically move from one cell to next, where they convert normal protein into bad ones, making healthy cells sick (which gets us to the very essence of the prion-like hypothesis).
The alpha-synuclein protein thus play an important role in the MSA disease process, but clumps of alpha synuclein protein are also found in brain cells of people that have Parkinson disease or Lewy Body Dementia. The fact that this one protein, alpha-synuclein, is involved in these seemingly different diseases hasn’t always made complete sense. What we have only discovered recently is that alpha-synuclein proteins tend to stick together in various ways so that they build different structures. In our food analogy, try to think again about cooking eggs: we can do much more than just boiling them. We can make them scrambled, sunny side up, medium, or well done – we can make different preparations by using the same protein. Research has shown that alpha-synuclein protein can stick together in different ways as well. For example, when we take the sticky clumps of protein that are formed in the brain of people with Parkinson disease and put them under the microscope they look like spaghetti. When we look at those found in the brain of people that have Multiple System Atrophy, they look flat and twisted, like tagliatelle, another type of pasta.
Why is it so important to know all this? Well, altogether, it has given us crucial clues as to why diseases like Parkinson Disease and MSA are so different but more importantly, how we can distinguish, diagnose and treat them. It also raises the idea that a single drug could be used for the treatment of multiple brain diseases. For instance, a drug that targets the sticky protein, reduces brain inflammation or improves metabolism could be used for treating MSA but also other brain disorders.
Emerging research has given us new and important insights that have dramatically deepened our understanding of MSA. MSA is not a genetic disease so challenges for the future will be to investigate how MSA is triggered, how it originates and where these sticky proteins in the central or peripheral nervous system originate. That way, if we are able to identify environmental risk factors, or risk genes, that would facilitate the disease to happen, we could start treatment much earlier and potentially slow its progression.
In conclusion, we need to stick with MSA and bring the disease to the forefront, through patient advocacy and scientific research. This is desperately needed for patients, their family and their caregivers. This will also accelerate our search for improved diagnoses and new drugs that could slow disease progression and eventually, stop the disease in its tracks or even reverse its course.