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The fundamental cause of multiple system atrophy (MSA) is a loss of oligodendroglial and neuronal cells in the brain and central nervous system. The loss of cells is gradual and progressive, leading to slowly worsening symptoms.
Degeneration is found in three parts of the nervous system: the basal ganglia, the cerebellum, and parts of the brain that regulate the autonomic nervous system. The basal ganglia are a set of nerves in the cerebrum that in part control voluntary movements. The cerebellum also controls voluntary muscle movements and contributes to balance.
However, what triggers the initial and ongoing loss of cells is unknown.
One older theory centers on trauma resulting in damage to the brain's gray matter. However, the glial cytoplasmic inclusions that were found to be the hallmark of the disease exist primarily in the white matter of the brain. Whether the inclusions are a definitive sign of injury is unknown. Myelin degeneration is also a contributor to the disease. Interestingly, specific symptoms of MSA can be correlated with loss of cells in specific regions of the brain.
In a small study in about 120 patients, half who had MSA and half who did not, it was found that the MSA patients had higher rates of potential exposure to metal dusts, plastics, pesticides, and organic solvents than the control group without MSA. The potential for exposure was determined based on their occupations. However, the patients' relatives were surveyed, also, and more of the relatives of the MSA group had symptoms of MSA than did the relatives of the control group.
Those results suggest that there may be a genetic vulnerability to MSA that can be activated by toxic environmental exposures.
In another study focusing on four Japanese families with multiple members affected by symptoms of MSA, researchers found that there was a genetic predisposition to the disease that was passed down through autosomal recessive inheritance. Further genetic studies have identified single nucleotide polymorphisms in a genetic location coding for alpha-snynuclein.
Alpha-synuclein is a protein found in abnormal quantities in the brain tissue of people with MSA. Its normal function is not well understood. Other nervous systems such as Parkinson's disease and Lewy body dementia also show abnormal build up of alpha-synuclein. A study published in 2015 in Proceedings of the National Academy of Sciences took things a step further and designated MSA as a prion disease, with alpha-synuclein as the infectious particle. Prions are self-propagating infectious proteins that change conformation. The first prion disease discovered was Creutzfeldt-Jakob disease (CJD), also known as Mad Cow Disease. To test whether alpha-synuclein might function as a prion in MSA, researchers from the University of California transferred diseased brain tissue into the brains of healthy mice. They found that the diseased brain extracts were infectious. In contrast, tissue from the brains of mice with Parkinson's disease did not transmit the disease to healthy mice. This would make MSA the first new prion disease discovered since CJD.