Lipid dysfunction and pathogenesis of multiple system atrophy

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.

Figure 1

A putative model of oligodendrocyte dysfunction in multiple system atrophy. (A) Normal oligodendrocytes with myelin covering the axon of a neuron. (B) Formation of glial cytoplasmic inclusions (GCIs), composed of aggregated α-synuclein, and demyelination. (C) Demyelination is followed by neurodegeneration and cell death.

Figure 2

Elevated expression of the lipid transporter ABCA8 in white matter regions of human brain. The expression of ABCA8 and ABCA1 (prototype in A subfamily) was measured in the superior frontal grey matter (GM) and white matter (WM) and inferior temporal GM and WM from six normal adults, comprising of three males and three females, by quantitative PCR; *p < 0.01 (Student’s t test).