From the Guidelines
Multiple system atrophy (MSA) is caused by the abnormal accumulation of a protein called alpha-synuclein in the brain, particularly in oligodendrocytes (cells that produce myelin), as noted in the most recent study 1. This accumulation forms inclusions called glial cytoplasmic inclusions, which damage and eventually kill nerve cells in specific areas of the brain including the basal ganglia, cerebellum, and brainstem. The exact trigger for this protein misfolding and accumulation remains unknown, though it appears to be a sporadic neurodegenerative disease rather than hereditary in most cases. While some research has suggested possible environmental factors or genetic susceptibilities, no definitive cause has been identified. Key characteristics of MSA include:
- Autonomic dysfunction (affecting blood pressure regulation, bladder control, and other automatic functions)
- Parkinsonism (movement problems)
- Cerebellar ataxia (coordination difficulties) Unlike Parkinson's disease, MSA does not respond well to levodopa therapy and progresses more rapidly, typically leading to significant disability within 5-10 years of diagnosis, as supported by the study 1. Additionally, the association between MSA and other conditions such as REM sleep behavior disorder (RBD) has been noted, with RBD being a common feature in patients with MSA, as reported in the study 1. However, the most recent and highest quality study 1 provides the most relevant information on the cause of MSA.
From the Research
Causes of Multiple System Atrophy
The exact cause of multiple system atrophy (MSA) is still not well understood. However, several studies have identified key factors that contribute to the development of this rare neurodegenerative disorder.
- The accumulation of aggregated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, is considered a hallmark of MSA 2, 3, 4, 5.
- Recent experimental evidence has confirmed the key role of alpha-synuclein aggregation in the pathogenesis of MSA 6.
- The underlying pathogenesis is still not well understood, but it is believed to involve a complex interplay of genetic and environmental factors 2.
Pathogenesis
The pathogenesis of MSA is characterized by:
- Selective atrophy and neuronal loss in striatonigral and olivopontocerebellar systems 3.
- The formation of glial cytoplasmic inclusions consisting of misfolded α-synuclein 3.
- A variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction 2.
Current Understanding
While the exact cause of MSA is still unknown, research has made significant progress in understanding the disease's pathogenesis and identifying potential therapeutic targets.
- Several studies have investigated the role of α-synuclein aggregation in MSA, and transgenic and toxic animal models have been developed to assess candidate drugs for the disease 6, 2.
- The standardization of diagnosis criteria and assessment procedures will allow large multicentre clinical trials to be conducted, which may lead to a better understanding of the disease and the development of effective treatments 6.