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Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed “Lewy Bodies” within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggr...

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Autores principales: Dumitriu, Alexandra, Golji, Javad, Labadorf, Adam T., Gao, Benbo, Beach, Thomas G., Myers, Richard H., Longo, Kenneth A., Latourelle, Jeanne C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722694/
https://www.ncbi.nlm.nih.gov/pubmed/26793951
http://dx.doi.org/10.1186/s12920-016-0164-y
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author Dumitriu, Alexandra
Golji, Javad
Labadorf, Adam T.
Gao, Benbo
Beach, Thomas G.
Myers, Richard H.
Longo, Kenneth A.
Latourelle, Jeanne C.
author_facet Dumitriu, Alexandra
Golji, Javad
Labadorf, Adam T.
Gao, Benbo
Beach, Thomas G.
Myers, Richard H.
Longo, Kenneth A.
Latourelle, Jeanne C.
author_sort Dumitriu, Alexandra
collection PubMed
description BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed “Lewy Bodies” within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking. METHODS: This study employed two state-of-the-art technologies, three-stage Mass Spectrometry Tandem Mass Tag Proteomics (12 PD, 12 controls) and RNA-sequencing transcriptomics (29 PD, 44 controls), evaluated in the context of PD GWAS implicated loci and microarray transcriptomics (19 PD, 24 controls). The technologies applied for this study were performed in a set of overlapping prefrontal cortex (Brodmann area 9) samples obtained from PD patients and sex and age similar neurologically healthy controls. RESULTS: After appropriate filters, proteomics robustly identified 3558 unique proteins, with 283 of these (7.9 %) significantly different between PD and controls (q-value < 0.05). RNA-sequencing identified 17,580 protein-coding genes, with 1095 of these (6.2 %) significantly different (FDR p-value < 0.05); only 166 of the FDR significant protein-coding genes (0.94 %) were present among the 3558 proteins characterized. Of these 166, eight genes (4.8 %) were significant in both studies, with the same direction of effect. Functional enrichment analysis of the proteomics results strongly supports mitochondrial-related pathways, while comparable analysis of the RNA-sequencing results implicates protein folding pathways and metallothioneins. Ten of the implicated genes or proteins co-localized to GWAS loci. Evidence implicating SNCA was stronger in proteomics than in RNA-sequencing analyses. CONCLUSIONS: We report the largest analysis of proteomics in PD to date, and the first to combine this technology with RNA-sequencing to investigate GWAS implicated loci. Notably, differentially expressed protein-coding genes were more likely to not be characterized in the proteomics analysis, which lessens the ability to compare across platforms. Combining multiple genome-wide platforms offers novel insights into the pathological processes responsible for this disease by identifying pathways implicated across methodologies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0164-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-47226942016-01-23 Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease Dumitriu, Alexandra Golji, Javad Labadorf, Adam T. Gao, Benbo Beach, Thomas G. Myers, Richard H. Longo, Kenneth A. Latourelle, Jeanne C. BMC Med Genomics Research Article BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed “Lewy Bodies” within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking. METHODS: This study employed two state-of-the-art technologies, three-stage Mass Spectrometry Tandem Mass Tag Proteomics (12 PD, 12 controls) and RNA-sequencing transcriptomics (29 PD, 44 controls), evaluated in the context of PD GWAS implicated loci and microarray transcriptomics (19 PD, 24 controls). The technologies applied for this study were performed in a set of overlapping prefrontal cortex (Brodmann area 9) samples obtained from PD patients and sex and age similar neurologically healthy controls. RESULTS: After appropriate filters, proteomics robustly identified 3558 unique proteins, with 283 of these (7.9 %) significantly different between PD and controls (q-value < 0.05). RNA-sequencing identified 17,580 protein-coding genes, with 1095 of these (6.2 %) significantly different (FDR p-value < 0.05); only 166 of the FDR significant protein-coding genes (0.94 %) were present among the 3558 proteins characterized. Of these 166, eight genes (4.8 %) were significant in both studies, with the same direction of effect. Functional enrichment analysis of the proteomics results strongly supports mitochondrial-related pathways, while comparable analysis of the RNA-sequencing results implicates protein folding pathways and metallothioneins. Ten of the implicated genes or proteins co-localized to GWAS loci. Evidence implicating SNCA was stronger in proteomics than in RNA-sequencing analyses. CONCLUSIONS: We report the largest analysis of proteomics in PD to date, and the first to combine this technology with RNA-sequencing to investigate GWAS implicated loci. Notably, differentially expressed protein-coding genes were more likely to not be characterized in the proteomics analysis, which lessens the ability to compare across platforms. Combining multiple genome-wide platforms offers novel insights into the pathological processes responsible for this disease by identifying pathways implicated across methodologies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0164-y) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-21 /pmc/articles/PMC4722694/ /pubmed/26793951 http://dx.doi.org/10.1186/s12920-016-0164-y Text en © Dumitriu et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Dumitriu, Alexandra
Golji, Javad
Labadorf, Adam T.
Gao, Benbo
Beach, Thomas G.
Myers, Richard H.
Longo, Kenneth A.
Latourelle, Jeanne C.
Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease
title Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease
title_full Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease
title_fullStr Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease
title_full_unstemmed Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease
title_short Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease
title_sort integrative analyses of proteomics and rna transcriptomics implicate mitochondrial processes, protein folding pathways and gwas loci in parkinson disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722694/
https://www.ncbi.nlm.nih.gov/pubmed/26793951
http://dx.doi.org/10.1186/s12920-016-0164-y
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