Multiple system atrophy (MSA) is a progressive neurodegenerative disease that affects a key area of the brain responsible for regulating vital bodily functions. As a result, patients with MSA develop orthostatic hypotension (a drop in blood pressure when moving from sitting to standing, which causes fainting or dizziness), difficulty regulating body temperature, impaired cardiovascular and respiratory function, and a loss of bladder or bowel control. In addition, patients may also have parkinsonian symptoms (difficulty moving their arms and legs, poor balance, slow movement, and sometimes tremors) or trouble with muscle coordination, which results in difficulty with chewing, focusing their eyes, or speaking.
The name multiple system atrophy was first proposed in 1969 by J.G. Graham and D.R. Oppenheimer as a reclassification of three previously separate diseases. Through their research, Graham and Oppenheimer determined that patients previously diagnosed with the diseases olivopontocerebellar atrophy (OPCA), Shy-Drager syndrome (SDS), or striatonigral degeneration (SND) were actually all MSA patients, they just had slightly different symptoms. In 1989, Matyas Papp and co-authors showed that OPCA, SDS, and SND patients all shared the same neuropathological inclusions in the brain (called glial cytoplasmic inclusions, or GCIs), supporting the reclassification of the three diseases as MSA. However, it was almost 10 years later, in 1998, that two independent research groups (one led by Maria Grazia Spillantini and the other by Koichi Wakabayashi) found that GCIs are full of the protein a-synuclein.
In a previous blog post, Dr. Wouter Peelearts described how this discovery led to a renaissance in MSA research. Additionally, he described the ability of a-synuclein proteins to misfold into a sticky conformation, which form large aggregates, or clumps, in the brains of MSA patients. This same underlying process is also thought to play a role in Parkinson’s disease (PD), which begs the question how are MSA and PD similar and how are they different? This is one of the research questions my laboratory is focused on, because the answer will help us determine if one therapeutic could be used to treat both MSA and PD patients, or if it is necessary to have a separate drug for each disease.
The leading hypothesis about how a-synuclein is different in these two diseases is called the strain hypothesis. As Dr. Peelaerts described in his blog post, aggregates of a-synuclein that have been isolated from the brains of MSA and PD patients look like different types of pasta under the microscope. If one were more like spaghetti and the other more like tagliatelle, we would say they were different strains (or shapes) of pasta. When we talk about infectious diseases, we are often describing different strains of things like viruses (such as influenza, or the flu), where strain differences arise from genetic mutations. For the flu, each strain will cause differences in symptoms and disease severity in a patient. For misfolded proteins, where there are no nucleic acids, the idea of strains cannot come from mutations. Instead, the shape that a protein misfolds into determines the disease strain, and each strain gives rise to a particular set of symptoms and pathology in a patient. As an analogy, one could describe normal, healthy a-synuclein in the brain as a circle, and in MSA patients, the circle misfolds into a triangle, but in PD patients, that circle becomes a square.
Interestingly, while MSA is a sporadic disease (meaning there is no known genetic cause), PD can be either sporadic or caused by mutations in a handful of genes, including the gene for a-synuclein. We have used this information to study the differences in the a-synuclein strains in the two diseases. For these experiments, we made human cells that contain either normal a-synuclein or a-synuclein with a mutation that causes PD, and then asked if the a-synuclein in MSA patient samples could cause the a-synuclein in the cells misfold (using our shape analogy above, can the MSA patient samples turn the a-synuclein circles into triangles?). We found that the MSA samples made normal a-synuclein misfold, but the results varied in cell lines with the mutations. Some of the mutant proteins (such as the A30P or A53T mutations) readily misfold in the presence of the MSA samples, but others (such as the E46K mutation) could not. Applying our shape analogy, if a-synuclein contains the E46K mutation, the circular protein can only misfold into a square (and cause PD). It cannot misfold into a triangle to cause MSA.
Why is this finding important? First, it tells us that the strain of a-synuclein that causes disease in MSA patients is different from the strain of a-synuclein that causes disease in PD patients. Second, this gives us a tool to evaluate potential drugs and determine if one drug can treat both diseases, or if the drug is strain specific. Knowing which patients are most likely to respond well to a treatment can help us design the best clinical trials possible, similar to how trials for cancer patients are often specific for tumor type.
To help defeat MSA, research in my laboratory at the University of Massachusetts Amherst is investigating how a-synuclein misfolding leads to MSA, and inventing strain-specific tools to support ongoing drug discovery efforts.