Multiple system atrophy: a clinical and neuropathological perspective

Abstract

Multiple system atrophy (MSA) is a neurodegenerative disease involving motor abnormalities that include akinesia, rigidity and postural instability. While improved diagnostic criteria have aided the accurate diagnosis of MSA, our understanding of the neuropathological aspects underlying MSA was bolstered by the identification of α-synuclein (α-syn) as the primary constituent of the abnormal protein aggregates observed in the brains of MSA patients. The generation of transgenic animal models of MSA coupled with an increasing understanding of the biochemical structure and function of α-syn has highlighted a number of key pathological pathways thought to underlie the neurodegeneration observed in MSA. This review summarizes key findings in the field, discusses current areas of debate, and describes current experimental approaches towards disease-modifying therapies.

Figure 1. Clinical and Neuropathological Characteristics of MSA

A number of clinical features are assessed before making a diagnosis of probable or possible MSA, including mood/cognitive alternations, ataxia/tremor, cardiovascular dysfunction and/or urogential dysfunction. However, a definitive diagnosis of MSA relies upon the neuropathological finding of α-syn positive inclusions in oligodendroglial cells, termed glial cytoplasmic inclusion (GCI). The presence of α-syn positive neuronal inclusions, termed neuronal cytoplasmic inclusions (NCI), has also been reported in the brains of MSA patients. Images of GCI and NCI reproduced, with permission, from .GCIs are visible as pale eosinophilic inclusions by hematoxylin and eosin staining in oligodendrocytes of post-mortem cortical tissue. Scale bars = 10µM.

Figure 2. Typical features of a transgenic mouse model of MSA

The central image is a schematic representation of a transgene in a typical transgenic (tg) model of MSA. In this particular model, human α-syn (hα-syn) is being driven by the oligodendrocyte-specific promoter MBP (myelin basic protein). (a) Comparison of the glial cell inclusions observed in post-mortem brain samples from MSA subjects and MBP hα-syn tg mice. Images are from the white matter tracts in the basal ganglia of a human case with typical MSA and MBP hα-syn tg mice (4 months of age). GCIs in the MSA case and the MBP hα-syn tg animal were positively immunostained with a polyclonal antibody against hα-syn (72–10), a monoclonal antibody against hα-syn (LB509), a monoclonal antibody against phospho-serine129 hα-syn (pser129) and an antibody against ubiquitin. Scale bar = 20µm. (b) Immunoreactivity of hα-syn in various brain regions in MBP hα-syn tg mice (4-months -of age), demonstrating widespread expression of hα-syn across these brain regions. Scale bars = 10µm. (c) Motor assessment in the pole test demonstrated only mild deficits in the MBP hα-syn tg mice at 3 months of age compared to controls (Nontg); however, at 6 months of age, these deficits were accentuated and remained similar at 12 months of age. Error bars are mean±SEM. *Significant difference compared with controls (p<0.05). Panels a–c adapted, with permission, from

Figure 3. Key mechanisms underlying neurodegeneration in MSA

(a) The precise mechanisms underlying neurodegeneration in MSA remain to be resolved, however, emerging results from studies on MSA and other α-synucleinopathies have highlighted a number of key pathways, including oxidative stress, perhaps as a result of mitochondrial dysfunction, environmental exposure to toxins, or a combination of both. (b) The pathological accumulation of oligodendroglial α-syn, possibly a result of cell-to-cell transfer of the protein, may potentiate neurodegeneration by a lack of trophic support for the neuron or by altered myelination. (c) The eventual macroscopic effect of these mechanisms is widespread atrophy in MSA brains. Image of the control brain is Nissel stained and adapted with permission from http://www.brains.rad.msu.edu, (supported by the US National Science Foundation). The image of the MSA brain is stained with Holzer stain, and reproduced, with permission from .