Alpha‐synuclein mRNA expression in oligodendrocytes in MSA

Yasmine T Asi,Stephen B Wharton,Janice L Holton,Paul R Heath,Andrew J Lees,Henry Houlden,Julie E Simpson,Tamas Revesz

doi:10.1002/glia.22653

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease presenting clinically with parkinsonian, cerebellar, and autonomic features. α-Synuclein (αsyn), encoded by the gene SNCA, is the main constituent of glial cytoplasmic inclusion (GCI) found in oligodendrocytes in MSA, but the methods of its accumulation have not been established. The aim of this study is to investigate alterations in regional and cellular SNCA mRNA expression in MSA as a possible substrate for GCI formation. Quantitative reverse transcription polymerase chain reaction (qPCR) was performed on postmortem brain samples from 15 MSA, 5 IPD, and 5 control cases to investigate regional expression in the frontal and occipital regions, dorsal putamen, pontine base, and cerebellum. For cellular expression analysis, neurons and oligodendrocytes were isolated by laser-capture microdissection from five MSA and five control cases. SNCA mRNA expression was not significantly different between the MSA, IPD and control cases in all regions (multilevel model, P = 0.14). After adjusting for group effect, the highest expression was found in the occipital cortex while the lowest was in the putamen (multilevel model, P < 0.0001). At the cellular level, MSA oligodendrocytes expressed more SNCA than control oligodendrocytes and expression in MSA neurons was slightly lower than that in controls, however, these results did not reach statistical significance. We have demonstrated regional variations in SNCA expression, which is higher in cortical than subcortical regions. This study is the first to demonstrate SNCA mRNA expression by oligodendrocytes in human postmortem tissue using qPCR and, although not statistically significant, could suggest that this may be increased in MSA compared to controls.

Highlights

Multiple system atrophy (MSA) is a progressive neurodegenerative disease that clinically presents with parkinsonian, cerebellar and autonomic features and pathologically with glial cytoplasmic inclusions (GCIs) found in oligodendrocytes, myelin damage, neuronal loss, and gliosis (Ahmed et al 2012; Ubhi et al 2011)
Regional SNCA mRNA expression was examined in the posterior frontal region, occipital region, dorsal putamen, pontine base, and cerebellar white matter of three MSA subtypes, IPD, and control cases (Fig. 1)
SNCA expression in neurons and oligodendrocytes isolated by laser capture was explored in the pontine base and cerebellar white matter, respectively, as these regions are affected in MSA

Summary

Introduction

Multiple system atrophy (MSA) is a progressive neurodegenerative disease that clinically presents with parkinsonian, cerebellar and autonomic features and pathologically with glial cytoplasmic inclusions (GCIs) found in oligodendrocytes, myelin damage, neuronal loss, and gliosis (Ahmed et al 2012; Ubhi et al 2011). Mutations and multiplications in SNCA, the gene encoding asyn, have been identified in some cases of familial PD and these have occasionally been found to have oligodendroglial inclusions resembling GCIs (Gwinn-Hardy et al 2000; Kiely et al 2013; Markopoulou et al 2008; Obi et al 2008). No mutations in SNCA have been associated with MSA (Gwinn-Hardy et al 2000; Kiely et al 2013; Markopoulou et al 2008; Obi et al 2008). In a small case study, SNCA mRNA levels in cortical regions

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