Abstract
Multiple system atrophy (MSA) is a neurodegenerative disease characterised by glial cytoplasmic inclusions (GCIs), containing α-synuclein. Mutated COQ2, encoding an enzyme essential for co-enzyme Q10 (CoQ10) biosynthesis, has been associated with MSA. CoQ10 is an electron carrier in the mitochondrial electron transport chain (ETC) and antioxidant. It has been shown to be deficient in MSA brain tissue, thus implicating mitochondrial dysfunction in MSA. To investigate mitochondrial dysfunction in MSA further we examined ETC activity in MSA and control brain tissue, compared with Parkinson’s disease (PD) where mitochondrial dysfunction is known to be important. Using cerebellar and occipital white matter ETC complex I, II/III and IV activities were measured spectrophotometrically, selected individual components of the ETC were assessed by immunoblotting and cellular complex IV activity was analysed by enzyme histochemistry. We show decreased complex II/III activity with increased complex I and IV activity in MSA cerebellar white matter. This corresponds with the deficit in CoQ10 previously described in MSA and reflects the high regional pathological burden of GCIs. This study highlights mitochondrial dysfunction in MSA pathogenesis, suggests an influence on selective regional vulnerability to disease and points to shared disease mechanisms in α-synucleinopathies.
Highlights
Multiple system atrophy (MSA) is a progressive and debilitating neurodegenerative disease presenting with combinations of clinical features including cerebellar ataxia (MSA-C), parkinsonism (MSA-P), autonomic dysfunction and pyramidal signs[1]
The activity of electron transport chain (ETC) complexes I, II/III and IV was measured in the cerebellar white matter, a region with large numbers of α-synuclein positive GCIs4,35 and compared with the occipital white matter, where glial cytoplasmic inclusions (GCIs) are sparse in MSA (Supplementary Fig. 1)[36,37]
All values are presented as the ratio between enzyme activity and citrate synthase (CS) activity to control for mitochondrial mass (Fig. 1)
Summary
Multiple system atrophy (MSA) is a progressive and debilitating neurodegenerative disease presenting with combinations of clinical features including cerebellar ataxia (MSA-C), parkinsonism (MSA-P), autonomic dysfunction and pyramidal signs[1]. In contrast with the neuronal Lewy body inclusions featured in PD and DLB, the neuropathological hallmark of MSA is the widespread presence of glial cytoplasmic inclusions (GCIs) composed of aggregated α-synuclein in oligodendrocytes[4,5,6,7]. MSA is regarded as a sporadic disease, genetic factors have been implicated in the aetiology of this disorder These include: copy number loss of C-terminal Src homology 2 Adapter Protein 2 (SHC2)[9], SNCA gene (synuclein alpha) single-nucleotide polymorphisms[10,11] and mutation in the CoQ2 gene which encodes for 4 hydroxbenzoate polyprenyltransferase (CoQ2), an enzyme involved in coenzyme Q10 (CoQ10) biosynthesis[12,13]. The observed decrease in cerebellar CoQ10 in MSA suggests that the function of the ETC may be disturbed in this disease[12,20,21]
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