Meszaros, Lisa and Riemenschneider, Markus J. and Gassner, Heiko and Marxreiter, Franz and von Hoersten, Stephan and Hoffmann, Alana and Winkler, Juergen (2021) Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy. ACTA NEUROPATHOLOGICA COMMUNICATIONS, 9 (1): 68. ISSN 2051-5960,
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Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (alpha-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 alpha-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-h alpha-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-h alpha-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-h alpha-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-h alpha-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-h alpha-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-h alpha-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CYTOPLASMIC INCLUSIONS; WHITE-MATTER; MOUSE MODEL; MYELIN; NEUROPATHOLOGY; CALBINDIN; CALCIUM; COORDINATION; MATURATION; PATHOLOGY; Multiple system atrophy; Cerebellar pathology; Cerebellar ataxia; Gait analysis |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Neuropathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Sep 2022 13:13 |
| Last Modified: | 13 Sep 2022 13:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47344 |
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