title: Exploring myelin dysfunction in multiple system atrophy.
abstract: Multiple system atrophy (MSA) is a rare, yet fatal neurodegenerative disease that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. MSA impacts on the autonomic nervous system affecting blood pressure, heart rate and bladder function, and the motor system affecting balance and muscle movement. The cause of MSA is unknown, no definitive risk factors have been identified, and there is no cure or effective treatment. The definitive pathology of MSA is the presence of α-synuclein aggregates in the brain and therefore MSA is classified as an α-synucleinopathy, together with Parkinson's disease and dementia with Lewy bodies. Although the molecular mechanisms of misfolding, fibrillation and aggregation of α-synuclein partly overlap with other α-synucleinopathies, the pathological pathway of MSA is unique in that the principal site for α-synuclein deposition is in the oligodendrocytes rather than the neurons. The sequence of pathological events of MSA is now recognized as abnormal protein redistributions in oligodendrocytes first, followed by myelin dysfunction and then neurodegeneration. Oligodendrocytes are responsible for the production and maintenance of myelin, the specialized lipid membrane that encases the axons of all neurons in the brain. Myelin is composed of lipids and two prominent proteins, myelin basic protein and proteolipid protein. In vitro studies suggest that aberration in protein distribution and lipid transport may lead to myelin dysfunction in MSA. The purpose of this perspective is to bring together available evidence to explore the potential role of α-synuclein, myelin protein dysfunction, lipid dyshomeostasis and ABCA8 in MSA pathogenesis.
authors.affiliation: Neuroscience Research Australia, Sydney, NSW 2031, Australia. ; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Wong
authors.affiliation: Neuroscience Research Australia, Sydney, NSW 2031, Australia. ; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Neuroscience Research Australia, Sydney, NSW 2031, Australia. ; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Woojin Scott
authors.initials: WS
authors.lastname: Kim
keywords: Multiple system atrophy; lipid dyshomeostasis; myelin; oligodendrocyte; α-synuclein