Oligodendroglial α-synucleinopathy-driven neuroinflammation in multiple system atrophy

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Multiple system atrophy (MSA) is characterized by neuroinflammation and alpha-synuclein (α-syn) inclusions in oligodendrocytes (GCIs).
• GCIs impair oligodendroglial function and lead to myelin loss, but the neuroinflammatory phenotype in MSA is not well understood.
• Existing knowledge gaps hinder effective therapeutic strategies for MSA.

Purpose of the Study:

• To investigate the link between neuroinflammation and oligodendroglial α-synucleinopathy in MSA.
• To determine the cellular and temporal characteristics of MSA-associated neuroinflammation.
• To elucidate the role of oligodendrocytes in initiating the myeloid immune response in MSA.

Main Methods:

• Analysis of post-mortem human MSA brain tissue (putamen).
• Assessment of a transgenic mouse model (MBP29-hα-syn) at pre-symptomatic and symptomatic stages.
• RNA sequencing of α-syn overexpressing primary oligodendrocytes and microdissected mouse brain tissue.

Main Results:

• MSA-associated neuroinflammation was restricted to white matter and correlated with α-syn inclusions.
• Pre-symptomatic MBP29-hα-syn mice showed increased, myeloid cell-driven neuroinflammation in α-syn-rich regions.
• Oligodendrocytes overexpressing α-syn exhibited gene expression profiles that attract and activate myeloid cells.

Conclusions:

• Neuroinflammation in MSA is primarily associated with oligodendroglial α-synucleinopathy and localized to white matter.
• An early crosstalk exists between oligodendrocytes with α-syn inclusions and myeloid cells, initiating a localized immune response.
• This early, localized inflammatory response in white matter is a key feature of MSA pathogenesis.