Models of multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a neurodegenerative disease with diverse clinical manifestations, including parkinsonism, cerebellar syndrome, and autonomic failure. Pathologically, MSA is characterized by glial cytoplasmic inclusions in oligodendrocytes, which contain fibrillary forms of α-synuclein. MSA is categorized as one of the α-synucleinopathy, and α-synuclein aggregation is thought to be the culprit of the disease pathogenesis. Studies on MSA pathogenesis are scarce relative to studies on the pathogenesis of other synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. However, recent developments in cellular and animal models of MSA, especially α-synuclein transgenic models, have driven advancements in research on this disease. Here, we review the currently available models of MSA, which include toxicant-induced animal models, α-synuclein-overexpressing cellular models, and mouse models that express α-synuclein specifically in oligodendrocytes through cell type-specific promoters. We will also discuss the results of studies in recently developed transmission mouse models, into which MSA brain extracts were intracerebrally injected. By reviewing the findings obtained from these model systems, we will discuss what we have learned about the disease and describe the strengths and limitations of the models, thereby ultimately providing direction for the design of better models and future research.

Fig. 1. Clinical characteristics of MSA.

The symptoms are subdivided into parkinsonian, cerebellar, and autonomic. Parkinsonian symptoms include motor symptoms, such as bradykinesia, tremor, and postural instability. Patients with more evident parkinsonism are considered to have the parkinsonian subtype of the disease (MSA-P). Patients with cerebellar symptoms, such as ataxia and cerebellar oculomotor dysfunction, are considered to have the cerebellar subtype of the disease (MSA-C). Both subtypes share common autonomic dysfunctions described above.

Fig. 2. The transmission model of α-synuclein in the brain.

Neuron-derived α-synuclein aggregates in the extracellular space are taken up by neighboring glial cells. Microglia and astrocytes, which secrete inflammatory molecules, are activated. Oligodendrocytes undergo demyelination, exposing neuronal axons that may retract or be degenerated by the hostile external environment, causing neurodegeneration.

Fig. 3. Summary of MSA models.

In vitro cell models have been used to express α-synuclein in oligodendrocytes. The effects of the addition of exogenous α-synuclein aggregates to oligodendrocytes have been studied in in vitro transmission models. Recent developments in stem cell technologies have allowed the growth of MSA-derived iPSCs and their differentiation into oligodendrocytes. Comparison studies of RNA, protein, and epigenetic changes in normal and patient-derived cells are ongoing. Animal models induced by the injection of toxins exhibit MSA-like symptoms, and oligodendrocyte-specific expression of α-synuclein has been achieved through the generation of tg mice and viral-mediated expression.