Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

Jürgen Winkler,Stephan Von Hörsten,Markus J Riemenschneider,Franz Marxreiter,Lisa Mészáros,Alana Hoffmann,Heiko Gassner

doi:10.1186/s40478-021-01166-x

Abstract

Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

Highlights

Multiple system atrophy (MSA) is an orphan, sporadic, and rapidly progressive neurodegenerative disease with equal gender distribution and a mean life expectancy of 6.2–10 years after diagnosis [1,2,3,4]
In addition to a widespread α-syn pathology, MBP29-hα-syn mice show a profound deficit of myelin and a distinct neuroinflammatory burden in the cbw followed by a substantial loss of Purkinje cells during disease progression
As the expression of human α-syn is controlled by the oligodendrocyte-specific murine myelin basic protein (MBP) promoter in MBP29-hα-syn mice, α-syn is—similar to human postmortem analysis—mainly localized within the white matter of the cerebellum

Summary

Introduction

Multiple system atrophy (MSA) is an orphan, sporadic, and rapidly progressive neurodegenerative disease with equal gender distribution and a mean life expectancy of 6.2–10 years after diagnosis [1,2,3,4]. Associated with GCI burden, demyelination, as well as neuroinflammation, neuronal cell loss in inferior olives, pontine nuclei and, in particular, degeneration of Purkinje cells are other important and progressive cerebellar hallmarks of MSA-C [8, 16,17,18]. This neuronal loss is linked to a severe limb and gait ataxia in MSA-C patients [19]

Methods

Results

Conclusion