Asi, YT; (2014) Pathogenic mechanisms in multiple system atrophy: a study of oligodendroglial pathology. Doctoral thesis , UCL (University College London).

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Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. The pathological hallmark of MSA is the glial cytoplasmic inclusion (GCI) found in oligodendrocytes and composed of many proteins, but with α-synuclein as the main constituent. GCIs are widespread in multiple brain regions and are hypothesized to play a primary role in the pathogenesis of MSA. Other pathological features of MSA include neuronal loss, glial nuclear inclusions, neuronal nuclear inclusions and gliosis. The first part of this thesis comprises of clinico-pathological studies exploring the role of oligodendroglial pathology, in addition to other pathologies, to the clinical profiles of different MSA subtypes. The subtypes studied are MSA with cognitive impairment, long duration MSA and minimal change MSA. The second part of the thesis addresses the question of the origins of α-synuclein in oligodendrocytes in MSA. The mechanisms by which α-synuclein accumulates in oligodendrocytes as GCIs have not been established, but are crucial to understanding the molecular pathology of the disease. Expression of α-synuclein protein and mRNA in oligodendrocytes and internalization of extracellular α-synuclein by oligodendrocytes were investigated in this thesis as possible mechanisms for GCI formation.

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