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Fig. 9 | Acta Neuropathologica Communications

Fig. 9

From: Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies

Fig. 9

The natural history of MSA-P in PLP-α-syn mice and humans in parallel. In human Parkinson variant MSA, the aetiology and early pathogenic events, presumably asymptomatic, remain unknown. The clinical diagnosis is usually determined with the onset of the motor symptoms (parkinsonism) and at that stage, retrospectively one identifies the pre-history of non-motor dysfunction including urogenital dysfunction, cardiovascular dysfunction, REM sleep behaviour disorder, and respiratory dysfunction [13]. Based on neuropathological studies, Halliday and co-workers proposed progression of the pathology in MSA-P including neuronal loss and GCIs in the basal ganglia and later on spreading in other brain areas [24]. Definite diagnosis of MSA and insights into the clinicopathological correlations is only possible post-mortem, however the identified spreading of GCIs, neuronal loss and gliosis at this end-stage of the disease can hardly answer the question how the disease progresses and what are the underlying mechanisms. Here we describe the disease progression in MSA mice (the PLP-α-syn transgenic mouse) that are genetically engineered to present oligodendroglial human α-syn overexpression leading to GCI-like pathology in the brains even at very early age. The GCI-load does not change with aging but differs among different brain areas (increasing from rostral to caudal regions, as shown by the colour gradient, see Fig. 2). MSA mice show a very early decrease in BDNF levels in the lower brainstem (see Fig. 7), which may be linked to the observed early degeneration of the brainstem nuclei involved in the regulation of autonomic functions, as indicated by the onset of neurogenic bladder dysfunction (1 [7]), REM sleep behaviour (2 [26]), cardiovascular failure (3 [35] and respiratory variability (4 [19]). Later on during the disease progression in the MSA mouse, the occurrence of soluble α-syn oligomeric species in the brain is accompanied by strong microglia activation which can be observed specifically in the midbrain (See Figs. 5 and 6), and leads to neuronal loss of dopaminergic neurons in SNc (see Fig. 4) [58]. Further on, the neurodegeneration spreads and involves other regions, including the striatum (Fig. 4). At this time robust progressive motor dysfunction (Fig. 3), resulting from the SND can be identified in the MSA mice. Notably, olivopontocerebellar atrophy, which underlies the cerebellar features in human MSA, can be triggered in the PLP-α-syn transgenic mouse only after exposure to exogenous stress like mitochondrial or proteasomal dysfunction [56, 57], but is not apparent due to the α-synuclein overexpression in oligodendrocytes per se. The striking overlap between the behavioural phenotype of the MSA mouse model and the clinical presentation in MSA-P patients suggests that the PLP-α-Syn transgenic mouse is a valuable preclinical tool to get insights into the pathogenesis of the disease and identify and validate targets of disease modification

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