Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy
Copyright policy )Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy
AbstractMultiple 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.
- University of Erlangen-Nuremberg Germany
- University Hospital Regensburg Germany
- University of California, San Francisco United States
- Universitätsklinikum Erlangen Germany
Male, 570, Cerebellar Ataxia, Clinical Sciences, 610, Mice, Transgenic, Neurodegenerative, Transgenic, Mice, Rare Diseases, Cerebellum/pathology [MeSH] ; Female [MeSH] ; Aged [MeSH] ; Cerebellar pathology ; Humans [MeSH] ; Multiple System Atrophy/pathology [MeSH] ; Middle Aged [MeSH] ; Multiple system atrophy ; Animals [MeSH] ; Mice, Transgenic [MeSH] ; Mice [MeSH] ; Multiple System Atrophy/complications [MeSH] ; Cerebellar ataxia ; Male [MeSH] ; Research ; Gait analysis ; alpha-Synuclein/genetics [MeSH] ; alpha-Synuclein/metabolism [MeSH] ; Cerebellar Ataxia/etiology [MeSH] ; Disease Models, Animal [MeSH], Cerebellum, DDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, RC346-429, Cerebellar ataxia, Aged, Parkinson's Disease, Biomedical and Clinical Sciences, Animal, Research, Neurosciences, Multiple system atrophy, Middle Aged, Multiple System Atrophy, Cerebellar pathology, Brain Disorders, Disease Models, Animal, Biochemistry and cell biology, Neurological, Disease Models, alpha-Synuclein, Gait analysis, Female, Biochemistry and Cell Biology, Neurology. Diseases of the nervous system
Male, 570, Cerebellar Ataxia, Clinical Sciences, 610, Mice, Transgenic, Neurodegenerative, Transgenic, Mice, Rare Diseases, Cerebellum/pathology [MeSH] ; Female [MeSH] ; Aged [MeSH] ; Cerebellar pathology ; Humans [MeSH] ; Multiple System Atrophy/pathology [MeSH] ; Middle Aged [MeSH] ; Multiple system atrophy ; Animals [MeSH] ; Mice, Transgenic [MeSH] ; Mice [MeSH] ; Multiple System Atrophy/complications [MeSH] ; Cerebellar ataxia ; Male [MeSH] ; Research ; Gait analysis ; alpha-Synuclein/genetics [MeSH] ; alpha-Synuclein/metabolism [MeSH] ; Cerebellar Ataxia/etiology [MeSH] ; Disease Models, Animal [MeSH], Cerebellum, DDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, RC346-429, Cerebellar ataxia, Aged, Parkinson's Disease, Biomedical and Clinical Sciences, Animal, Research, Neurosciences, Multiple system atrophy, Middle Aged, Multiple System Atrophy, Cerebellar pathology, Brain Disorders, Disease Models, Animal, Biochemistry and cell biology, Neurological, Disease Models, alpha-Synuclein, Gait analysis, Female, Biochemistry and Cell Biology, Neurology. Diseases of the nervous system
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).11 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!