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Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy

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Abstract

Multiple system atrophy (MSA) is a distinct member of a group of neurodegenerative diseases known as α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein in the brain. MSA is unique in that the principal site for α-synuclein deposition is in the oligodendrocytes rather than neurons. The cause of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Brain transcriptome perturbations during the onset and progression of MSA are mostly unknown. Using RNA sequencing, we performed a comparative transcriptome profiling analysis of the grey matter (GM) and white matter (WM) of the frontal cortex of MSA and control brains. The transcriptome sequencing revealed increased expression of the alpha and beta haemoglobin genes in MSA WM, decreased expression of the transthyretin (TTR) gene in MSA GM and numerous region-specific long intervening non-coding RNAs (lincRNAs). In contrast, we observed only moderate changes in the expression patterns of the α-synuclein (SNCA) gene, which confirmed previous observations by other research groups. Our study suggests that at the transcriptional level, MSA pathology may be related to increased iron levels in WM and perturbations of the non-coding fraction of the transcriptome.

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Acknowledgments

Authors wish to thank Bei Jun Chen for her contribution to GO term enrichment analysis and generation of Suppl. Fig. 1 and Caroline Janitz for her expert advice regarding Illumina sequencing. Tissues were received from the Sydney Brain Bank at Neuroscience Research Australia and the New South Wales Tissue Resource Centre at the University of Sydney which are supported by the National Health and Medical Research Council of Australia (NHMRC), University of New South Wales, Neuroscience Research Australia, Schizophrenia Research Institute and National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725). This research was supported by the National Health and Medical Research Council of Australia (Project grant #1022325 to WSK and Fellowship #630434 to GMH) and Brain Foundation Australia (to MJ).

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Authors and Affiliations

  1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    James D. Mills & Michael Janitz

  2. Neuroscience Research Australia, Sydney, NSW, 2031, Australia

    Woojin S. Kim & Glenda M. Halliday

  3. School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    Woojin S. Kim & Glenda M. Halliday

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  1. James D. Mills
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  4. Michael Janitz
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Correspondence to Michael Janitz.

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Supplementary Figure 1

Schematic presentation of the RNA-Seq bioinformatics analytical pipeline. Sample 1 and 2 indicate respective biological conditions to be compared such as MSA WM, MSA GM, MSA control and WM control. Please refer to the Methods section for details. (PDF 323 kb)

Supplementary Figure 2

RT-qPCR validation of the TTR and HB genes expression pattern in GM and WM MSA samples. TTR was down-regulated 3.3-fold in MSA GM when compared to control (Con) GM (p-value<0.05). HBA1, HBA2 and HBB were up-regulated 9-, 6.3- and 10.4-fold, respectively, in MSAWM comparing to control WM (p-value<0.05). PSMB4 was used as a reference gene to normalize the expression levels of linc00263 before comparisons between tissue types were made. Expression levels were calculated using 2-ΔCt and fold-change was calculated using the 2-ΔΔCt method [50]. (PDF 50 kb)

Supplementary Table 1

Full list of genes and isoforms which show significant change in expression in MSA GM and MSA WM including GO terms enrichment analysis. (XLSX 330 kb)

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Mills, J.D., Kim, W.S., Halliday, G.M. et al. Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy. Neurogenetics 16, 107–122 (2015). https://doi.org/10.1007/s10048-014-0430-0

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