Pathophysiology and Mechanisms of Multiple System Atrophy

Multiple system atrophy (MSA) is a relentlessly progressive adult-onset synucleinopathy characterised by the intracytoplasmic accumulation of α-synuclein in oligodendrocytes, manifesting as glial cytoplasmic inclusions (GCIs). This aggregation event is accompanied by widespread neuronal loss, demyelination and gliosis across striatonigral, olivopontocerebellar and autonomic pathways. Pathogenic α-synuclein deposition stems from a combination of impaired protein clearance—particularly via the autophagy–lysosomal system—mitochondrial dysfunction linked to coenzyme Q10 deficiency and COQ2 mutations, and possible neuronal-to-oligodendroglial transfer or de novo oligodendrocyte expression of α-synuclein. Concomitant dysregulation of lipid metabolism weakens myelin integrity, while epigenetic alterations in white matter, notably DNA methylation changes, affect gene networks governing Wnt signalling, endoplasmic reticulum stress and RNA processing. Neuroinflammation, driven by microglial activation and peripheral T cell infiltration, not only responds to but may also promote propagation of α-synuclein pathology. The dynamic interplay between glial, neuronal and immune compartments creates a feed-forward cycle of degeneration, underscoring the need for integrated strategies—ranging from aggregation inhibitors and immunomodulators to mitochondrial enhancers and epigenetic therapies—to halt or reverse disease progression.

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Pathophysiology and Mechanisms of Multiple System Atrophy publication trend

The graph below shows the total number of articles in pathophysiology and mechanisms of multiple system atrophy across all publications each year (not limited to Nature Index journals).

Technical terms

Glial cytoplasmic inclusion (GCI): Intracellular aggregates of misfolded α-synuclein within oligodendrocytes, defining the pathological hallmark of MSA.

Autophagy–lysosomal pathway: Cellular mechanism for degradation and recycling of proteins and organelles; its dysfunction leads to pathological protein accumulation.

Synucleinopathy: Group of neurodegenerative diseases characterised by abnormal α-synuclein aggregation, including MSA, Parkinson’s disease and dementia with Lewy bodies.

Epigenetic regulation: Heritable modifications—such as DNA methylation—that alter gene expression without changing the DNA sequence, influencing neurodegenerative processes.

Microglial activation: Reactive transformation of CNS-resident immune cells, marked by cytokine release and morphological changes that can exacerbate neuronal injury.

References

1. Distinct ultrastructural phenotypes of glial and neuronal alpha-synuclein inclusions in multiple system atrophy. Brain (2024).
2. DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson’s disease, and progressive supranuclear palsy: a cross-comparative investigation. Acta Neuropathologica (2024).
3. Alpha‐synuclein mRNA expression in oligodendrocytes in MSA. Glia (2014).
4. Neuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation. Frontiers in Cellular Neuroscience (2015).
5. T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease. Acta Neuropathologica (2020).
6. Increased Neuronal α-Synuclein Pathology Associates with Its Accumulation in Oligodendrocytes in Mice Modeling α-Synucleinopathies. PLOS ONE (2012).
7. Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathologica Communications (2014).