Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype
Lisa Mészáros1, Markus J Riemenschneider2, Heiko Gassner1
1Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
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.
Insights
This study shows the MBP29-hα-syn mouse model effectively mimics Multiple System Atrophy Cerebellar type (MSA-C) pathology, including cerebellar ataxia. This validated model is crucial for developing new treatments for MSA-C.
Area of Science:
- Neuroscience
- Neuropathology
- Genetics
Background:
- Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disorder.
- Two main subtypes exist: MSA-parkinsonian (MSA-P) and MSA-cerebellar (MSA-C).
- Existing mouse models primarily replicate MSA-P, leaving MSA-C poorly modeled.
Purpose of the Study:
- To investigate if the MBP29-hα-syn mouse model recapitulates key features of MSA-C.
- To compare neuropathological findings in human MSA-C tissue with the mouse model.
- To assess the utility of this model for preclinical research in MSA-C.
Main Methods:
- Analysis of post-mortem human MSA-C cerebellar tissue.
- Phenotypic characterization of MBP29-hα-syn mice.
- Structural analysis of the hindbrain and functional gait assessment (Catwalk XT).
Main Results:
- Human MSA-C tissue showed glial cytoplasmic inclusions (GCIs), myelin deficits, and Purkinje cell loss.
- MBP29-hα-syn mice exhibited GCIs, myelin deficits, and Purkinje cell loss, mirroring MSA-C.
- Mice displayed gait abnormalities indicative of cerebellar ataxia, including reduced speed and altered stride.
Conclusions:
- The MBP29-hα-syn mouse model accurately replicates critical neuropathological and functional aspects of MSA-C.
- This model serves as a valuable preclinical tool for testing therapeutic interventions for MSA-C.
- Further research using this model can advance understanding and treatment of cerebellar MSA.
