Reductions in COQ2 Expression Relate to Reduced ATP Levels in Multiple System Atrophy Brain.

Jen-Hsiang T Hsiao,Sivaraman Purushothuman,Woojin Scott Kim,Poul H Jensen,Glenda M Halliday

doi:10.3389/fnins.2019.01187

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease clinically characterized by parkinsonism and cerebellar ataxia, and pathologically by oligodendrocyte α-synuclein inclusions. Genetic variants of COQ2 are associated with an increased risk for MSA in certain populations. Also, deficits in the level of coenzyme Q10 and its biosynthetic enzymes are associated with MSA. Here, we measured ATP levels and expression of biosynthetic enzymes for coenzyme Q10, including COQ2, in multiple regions of MSA and control brains. We found a reduction in ATP levels in disease-affected regions of MSA brain that associated with reduced expression of COQ2 and COQ7, supporting the concept that abnormalities in the biosynthesis of coenzyme Q10 play an important role in the pathogenesis of MSA.

Highlights

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic dysfunction (Wenning et al, 1997; Ozawa et al, 2001) and pathologically by abnormal α-synuclein deposition in oligodendrocytes, called glial cytoplasmic inclusions (GCIs) (Papp et al, 1989; Spillantini et al, 1997; Gai et al, 1998)
We confirmed, by immunohistochemistry, that GCIs were present in the disease-affected regions of MSA brain (Figure 1B)
In vivo magnetic spectroscopic imaging evaluation of ATP levels in the basal ganglia in early MSA patients showed no significant reduction (Stamelou et al, 2015), but our results suggest that ATP levels are affected in the cerebellar pathways, at least over the disease course

Summary

INTRODUCTION

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic dysfunction (Wenning et al, 1997; Ozawa et al, 2001) and pathologically by abnormal α-synuclein deposition in oligodendrocytes, called glial cytoplasmic inclusions (GCIs) (Papp et al, 1989; Spillantini et al, 1997; Gai et al, 1998). While the general consensus is that MSA is a highly sporadic disease, emerging evidence has suggested rare genetic variants increase susceptibility, this appears to be dependent on the geographical distribution of sample patients (Soma et al, 2006; Hara et al, 2007; Stemberger et al, 2011; Multiple-System Atrophy Research Collaboration, 2013). One such gene is COQ2 (Multiple-System Atrophy Research Collaboration, 2013). We assessed whether the levels of ATP are perturbed in MSA and reassessed whether biosynthetic enzymes for coenzyme Q10, including COQ2, are involved

MATERIALS AND METHODS

RESULTS AND DISCUSSION

ETHICS STATEMENT