Abstract
Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of α-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. α-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. α-Synuclein aggregation in neurons is a well-characterized feature of Parkinson’s disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of α-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of α-synuclein aggregation. However, MSA is distinct from other α-synucleinopathies in a number of respects, not least the disparate cellular focus of α-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of α-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.
Highlights
Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic failure
The purpose of this review is to explore the significance of brain lipid metabolism in MSA pathogenesis
Sphingomyelin is an important glycosphingolipid component of the myelin membrane. In sum these results strongly suggest that ABCA8 regulates lipid metabolism in oligodendrocytes and potentially plays a role in myelin formation and maintenance
Summary
Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic failure. Α-syn appears to have diverse roles in brain lipid metabolism, including lipid-mediated signaling pathways and fatty acid trafficking to key phospholipid pools integral to the structure and function of biological membranes These functions may be integral to an understanding of the reciprocal influences of lipid membrane composition on pathological α-syn aggregation as discussed below. As deficiencies in coenzyme Q10 are known to induce oxidative stress [77,78], this poses another mechanism by which peripheral lipid dyshomeostasis could contribute to the pathogenesis of MSA This possibility is in accordance with the finding that COQ2 mutations were more common in MSA patients with predominant cerebellar involvement [10], as a previous study has shown the cerebellum in both rats and humans contains the lowest concentration of coenzyme Q10 in the brain [122]. It appears the cerebellum may have heightened vulnerability to the damaging consequences of mutations in the COQ2 gene
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
