Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease
Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throug...
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| Veröffentlicht in: | PloS one 2013-11, Vol.8 (11), p.e76162-e76162 |
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| creator | Kikuchi, Masataka Ogishima, Soichi Miyamoto, Tadashi Miyashita, Akinori Kuwano, Ryozo Nakaya, Jun Tanaka, Hiroshi |
| description | Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system. |
| doi_str_mv | 10.1371/journal.pone.0076162 |
| format | Article |
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Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0076162</identifier><identifier>PMID: 24348898</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Advertising executives ; Aged ; Aged, 80 and over ; Aging ; Algorithms ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid ; Bioinformatics ; Brain ; Brain research ; Cell death ; Constituents ; Cortex (entorhinal) ; Cortex (frontal) ; Databases, Factual ; Datasets ; Dementia ; Dementia disorders ; Development and progression ; Disease Progression ; Frontal gyrus ; Gene expression ; Gene regulation ; Genes ; Genomics ; Hip ; Humans ; Informatics ; Memory ; Middle Aged ; Modules ; Neurons ; NMR ; Nuclear magnetic resonance ; Ontology ; Pathogenesis ; Patients' rights ; Proteasomes ; Proteins ; Tau protein ; Transcription ; Ubiquitin ; Young Adult</subject><ispartof>PloS one, 2013-11, Vol.8 (11), p.e76162-e76162</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Kikuchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Kikuchi et al 2013 Kikuchi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-9533e36babccbadb6da92d889c8e6a0009dbf55ebfa273460bb5fff0e78e6b373</citedby><cites>FETCH-LOGICAL-c692t-9533e36babccbadb6da92d889c8e6a0009dbf55ebfa273460bb5fff0e78e6b373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858171/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858171/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24348898$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Csermely, Peter</contributor><creatorcontrib>Kikuchi, Masataka</creatorcontrib><creatorcontrib>Ogishima, Soichi</creatorcontrib><creatorcontrib>Miyamoto, Tadashi</creatorcontrib><creatorcontrib>Miyashita, Akinori</creatorcontrib><creatorcontrib>Kuwano, Ryozo</creatorcontrib><creatorcontrib>Nakaya, Jun</creatorcontrib><creatorcontrib>Tanaka, Hiroshi</creatorcontrib><title>Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.</description><subject>Adult</subject><subject>Advertising executives</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aging</subject><subject>Algorithms</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Bioinformatics</subject><subject>Brain</subject><subject>Brain research</subject><subject>Cell death</subject><subject>Constituents</subject><subject>Cortex (entorhinal)</subject><subject>Cortex (frontal)</subject><subject>Databases, Factual</subject><subject>Datasets</subject><subject>Dementia</subject><subject>Dementia disorders</subject><subject>Development and progression</subject><subject>Disease Progression</subject><subject>Frontal gyrus</subject><subject>Gene 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Akinori</au><au>Kuwano, Ryozo</au><au>Nakaya, Jun</au><au>Tanaka, Hiroshi</au><au>Csermely, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-11-15</date><risdate>2013</risdate><volume>8</volume><issue>11</issue><spage>e76162</spage><epage>e76162</epage><pages>e76162-e76162</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24348898</pmid><doi>10.1371/journal.pone.0076162</doi><tpages>e76162</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Advertising executives Aged Aged, 80 and over Aging Algorithms Alzheimer Disease - pathology Alzheimer's disease Amyloid Bioinformatics Brain Brain research Cell death Constituents Cortex (entorhinal) Cortex (frontal) Databases, Factual Datasets Dementia Dementia disorders Development and progression Disease Progression Frontal gyrus Gene expression Gene regulation Genes Genomics Hip Humans Informatics Memory Middle Aged Modules Neurons NMR Nuclear magnetic resonance Ontology Pathogenesis Patients' rights Proteasomes Proteins Tau protein Transcription Ubiquitin Young Adult |
| title | Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease |
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