Role of the Long Non-Coding RNA MAPT-AS1 in Regulation of Microtubule Associated Protein Tau (MAPT) Expression in Parkinson's Disease.

Kirsten G Coupland,Woojin S Kim,John B J Kwok,Glenda M Halliday,Marianne Hallupp,Carol Dobson-Stone,Patrick Lewis

doi:10.1371/journal.pone.0157924

Kirsten G Coupland, Woojin S Kim + Show 5 more

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https://doi.org/10.1371/journal.pone.0157924

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Journal: PloS one	Publication Date: Jun 23, 2016
Citations: 61	License type: CC BY 4.0

Affiliation: Neuroscience Research Australia, UNSW Sydney

Abstract

Studies investigating the pathogenic role of the microtubule associated protein tau (MAPT) gene in Parkinson’s disease (PD) have indicated that DNA methylation of the promoter region is aberrant in disease, leading to dysregulated MAPT expression. We examined two potential regulators of MAPT gene expression in respect to PD, a promoter-associated long non-coding RNA MAPT-AS1, and DNA methyltransferases (DNMTs), enzymes responsible for new and maintenance of DNA methylation. We assessed the relationship between expression levels of MAPT and the candidate MAPT-AS1, DNMT1, DNMT3A and DNMT3B transcripts in four brain regions with varying degrees of cell loss and pathology (putamen, anterior cingulate cortex, visual cortex and cerebellum) in N = 10 PD and N = 10 controls. We found a significant decrease in MAPT-AS1 expression in PD (p = 7.154 x 10−6). The transcript levels of both MAPT-AS1 (p = 2.569 x 10−4) and DNMT1 (p = 0.001) correlated with those of MAPT across the four brain regions, but not with each other. Overexpression of MAPT-AS1 decreased MAPT promoter activity by ∼2.2 to 4.3 fold in an in vitro luciferase assay performed in two cell lines (p ≤ 2.678 x 10−4). Knock-down expression of MAPT-AS1 led to a 1.3 to 6.3 fold increase in methylation of the endogenous MAPT promoter (p ≤ 0.011) and a 1.2 to 1.5 fold increased expression of the 4-repeat MAPT isoform transcript (p ≤ 0.013). In conclusion, MAPT-AS1 and DNMT1 have been identified as potential epigenetic regulators of MAPT expression in PD across four different brain regions. Our data also suggest that increased MAPT expression could be associated with disease state, but not with PD neuropathology severity.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterised by tremor and bradykinesia, that affects 2% of the population over the age of 65 [1]
Microtubule-associated protein tau, a protein that aids in stabilising the axonal cytoskeleton, is interesting as it has been indicated as a susceptibility gene in other neurodegenerative conditions such as progressive supranuclear palsy [11], and microtubule-associated protein tau (MAPT) mutations are a cause of monogenic frontotemporal dementia [12]
In addition to the basic demographic factors such as age (Table 2), we examined the effect of disease state on the transcript levels of our five genes of interest, MAPT, MAPT-AS1, DNMT1, DNMT3A and DNMT3B

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterised by tremor and bradykinesia, that affects 2% of the population over the age of 65 [1]. Monogenic forms of PD have been linked to mutations in genes including α-synuclein (SNCA) [3], leucinerich repeat kinase 2 (LRRK2) [4] and parkin (PARK2) [5]. These monogenic forms, explain only 6% of PD cases, while the remaining are ‘idiopathic’ or sporadic, as their aetiology is unknown [6]. Microtubule-associated protein tau (tau), a protein that aids in stabilising the axonal cytoskeleton, is interesting as it has been indicated as a susceptibility gene in other neurodegenerative conditions such as progressive supranuclear palsy [11], and MAPT mutations are a cause of monogenic frontotemporal dementia [12]. The MAPT promoter has been shown to be aberrantly methylated in both leukocyte and brain tissue of PD patients [17, 18]

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