gms | German Medical Science

Introduction: Multiple system atrophy (MSA) is an atypical parkinsonian disorder associated with accumulation of α-synuclein (aSyn) in oligodendroglial cytoplasmic inclusions (GCIs). GCI pathology is accompanied by a severe astro- and microgliosis as well as myelin loss contributing to secondary axonal dysfunction and neuronal cell death.

Objectives: With this study we want to understand the interplay of neuroinflammation and aSyn-related oligodendrogliopathy.

Patients, Material & Methods: We analyzed transgenic mice expressing high levels of human aSyn under the control of a murine myelin basic protein promoter (MBP29-hα-syn) and quantified the number of Iba1+ microglia as well as the aSyn load in the corpus callosum, striatum, and motor cortex. Moreover, we analyzed the putamen of human post-mortem brain tissue of MSA-P (parkinsonian type) patients (n=6, age: 64±6 years) and controls (n=6, age: 60±9 years) to determine the number of CD68+ microglia and the extent of aSyn pathology in gray and white matter regions.

Results: The number of white matter Iba1+ microglial cells was profoundly increased in the corpus callosum of MBP29-hα-syn mice. A moderate increase was detected in the striatum, whereas no difference was present in the motor cortex. Similarly, a higher aSyn load was observed in the corpus callosum of MBP29-hα-syn mice in comparison to the motor cortex and striatum. Intriguingly, matching these findings in the MSA model, we detected an increased number of CD68+ microglia associated with an increased aSyn density in the white matter of MSA-P patients.

Conclusion: aSyn-positive oligodendrocytes are accompanied with microglia activation present in white matter regions of the adult forebrain. These findings imply that there may be an oligodendroglial-microglial crosstalk in which aSyn or oligodendrocytes with GCIs result in a widespread pro-inflammatory environment in MSA, predominantly in white matter regions.