Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease
The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides result...
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| description | The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.
We have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.
We have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD. |
| doi_str_mv | 10.1371/journal.pone.0137691 |
| format | Article |
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We have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.
We have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0137691</identifier><identifier>PMID: 26367392</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adapter proteins ; Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Peptides - biosynthesis ; Amyloid beta-Peptides - genetics ; Amyloid precursor protein ; Animals ; Apoptosis ; Axon guidance ; Axons ; Biology ; Brain ; Brain - metabolism ; Brain - pathology ; Cancer ; Cell cycle ; Cell death ; Cognitive ability ; CREB-binding protein ; CREB-Binding Protein - genetics ; CREB-Binding Protein - metabolism ; Cyclic AMP response element-binding protein ; Disease Models, Animal ; Drosophila ; Drosophila melanogaster ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Fruit flies ; Function analysis ; Genes ; Humans ; Insects ; Kinases ; Mice, Transgenic ; Mortality ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Neuroprotection ; Peptide Fragments - biosynthesis ; Peptide Fragments - genetics ; Phenotypes ; Photoreceptors ; Polyglutamine ; Polypeptides ; Proteins ; Retina ; Retina - metabolism ; Retina - pathology ; Senile plaques ; Structure-function relationships ; Transgenic ; Trinucleotide repeat diseases</subject><ispartof>PloS one, 2015-09, Vol.10 (9), p.e0137691</ispartof><rights>2015 Cutler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (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>2015 Cutler et al 2015 Cutler et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-3393acbac71aef9b4a23ab24890b15fd4cdb9c5657db31613f7c786906b765db3</citedby><cites>FETCH-LOGICAL-c526t-3393acbac71aef9b4a23ab24890b15fd4cdb9c5657db31613f7c786906b765db3</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/PMC4569556/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569556/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26367392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pandey, Udai</contributor><creatorcontrib>Cutler, Timothy</creatorcontrib><creatorcontrib>Sarkar, Ankita</creatorcontrib><creatorcontrib>Moran, Michael</creatorcontrib><creatorcontrib>Steffensmeier, Andrew</creatorcontrib><creatorcontrib>Puli, Oorvashi Roy</creatorcontrib><creatorcontrib>Mancini, Greg</creatorcontrib><creatorcontrib>Tare, Meghana</creatorcontrib><creatorcontrib>Gogia, Neha</creatorcontrib><creatorcontrib>Singh, Amit</creatorcontrib><title>Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.
We have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.
We have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.</description><subject>Adapter proteins</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - biosynthesis</subject><subject>Amyloid beta-Peptides - genetics</subject><subject>Amyloid precursor protein</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Axon guidance</subject><subject>Axons</subject><subject>Biology</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cognitive ability</subject><subject>CREB-binding protein</subject><subject>CREB-Binding Protein - genetics</subject><subject>CREB-Binding Protein - metabolism</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Disease Models, Animal</subject><subject>Drosophila</subject><subject>Drosophila melanogaster</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Fruit flies</subject><subject>Function analysis</subject><subject>Genes</subject><subject>Humans</subject><subject>Insects</subject><subject>Kinases</subject><subject>Mice, Transgenic</subject><subject>Mortality</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurons</subject><subject>Neuroprotection</subject><subject>Peptide Fragments - biosynthesis</subject><subject>Peptide Fragments - genetics</subject><subject>Phenotypes</subject><subject>Photoreceptors</subject><subject>Polyglutamine</subject><subject>Polypeptides</subject><subject>Proteins</subject><subject>Retina</subject><subject>Retina - metabolism</subject><subject>Retina - pathology</subject><subject>Senile plaques</subject><subject>Structure-function relationships</subject><subject>Transgenic</subject><subject>Trinucleotide repeat diseases</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUk1vEzEQXSEQLYV_gMASB8ohwR9re32p1KQBKhWoCpwt2-tNHDnrxd6tlP76Os22ahEHy6M3b55nxq8o3iI4RYSjz-swxFb5aRdaO4UZYgI9Kw6RIHjCMCTPH8UHxauU1hBSUjH2sjjAjDBOBD4slmcxpNCtnFdgsbXge6itB30Av_qh3oIfdoihi6G3pnfXFlwFb0FowPxqMQMz19auXYLLXd614Hg-u_wEcnDqb1bWbWz8mMCZS1Yl-7p40Sif7JvxPir-fFn8nn-bXPz8ej4_vZgYilk_IUQQZbQyHCnbCF0qTJTGZSWgRrSpS1NrYSijvNYEMUQabnjFBGSaM5qxo-L9XrfzIclxR0kijgSuKOQoM873jDqoteyi26i4lUE5eQeEuJQq9s54K7luGMl7QkKLsmRCNZgjhDHBEDLR0Kx1Mr426I2tjW37qPwT0aeZ1q3kMlzLkjJBKcsCx6NADH8Hm3q5cclY71Vrw3DXN-YVzCdTP_xD_f905Z5l8r-maJuHZhCUO9_cV8mdb-Tom1z27vEgD0X3RiG3ljC_LA</recordid><startdate>20150914</startdate><enddate>20150914</enddate><creator>Cutler, Timothy</creator><creator>Sarkar, Ankita</creator><creator>Moran, Michael</creator><creator>Steffensmeier, Andrew</creator><creator>Puli, Oorvashi Roy</creator><creator>Mancini, Greg</creator><creator>Tare, Meghana</creator><creator>Gogia, Neha</creator><creator>Singh, Amit</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150914</creationdate><title>Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease</title><author>Cutler, Timothy ; Sarkar, Ankita ; Moran, Michael ; Steffensmeier, Andrew ; Puli, Oorvashi Roy ; Mancini, Greg ; Tare, Meghana ; Gogia, Neha ; Singh, Amit</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-3393acbac71aef9b4a23ab24890b15fd4cdb9c5657db31613f7c786906b765db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adapter proteins</topic><topic>Alzheimer Disease - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cutler, Timothy</au><au>Sarkar, Ankita</au><au>Moran, Michael</au><au>Steffensmeier, Andrew</au><au>Puli, Oorvashi Roy</au><au>Mancini, Greg</au><au>Tare, Meghana</au><au>Gogia, Neha</au><au>Singh, Amit</au><au>Pandey, Udai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-09-14</date><risdate>2015</risdate><volume>10</volume><issue>9</issue><spage>e0137691</spage><pages>e0137691-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.
We have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.
We have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26367392</pmid><doi>10.1371/journal.pone.0137691</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1719285071 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adapter proteins Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Peptides - biosynthesis Amyloid beta-Peptides - genetics Amyloid precursor protein Animals Apoptosis Axon guidance Axons Biology Brain Brain - metabolism Brain - pathology Cancer Cell cycle Cell death Cognitive ability CREB-binding protein CREB-Binding Protein - genetics CREB-Binding Protein - metabolism Cyclic AMP response element-binding protein Disease Models, Animal Drosophila Drosophila melanogaster Drosophila Proteins - genetics Drosophila Proteins - metabolism Fruit flies Function analysis Genes Humans Insects Kinases Mice, Transgenic Mortality Neurodegeneration Neurodegenerative diseases Neurons Neuroprotection Peptide Fragments - biosynthesis Peptide Fragments - genetics Phenotypes Photoreceptors Polyglutamine Polypeptides Proteins Retina Retina - metabolism Retina - pathology Senile plaques Structure-function relationships Transgenic Trinucleotide repeat diseases |
| title | Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer's Disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T19%3A21%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Drosophila%20Eye%20Model%20to%20Study%20Neuroprotective%20Role%20of%20CREB%20Binding%20Protein%20(CBP)%20in%20Alzheimer's%20Disease&rft.jtitle=PloS%20one&rft.au=Cutler,%20Timothy&rft.date=2015-09-14&rft.volume=10&rft.issue=9&rft.spage=e0137691&rft.pages=e0137691-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0137691&rft_dat=%3Cproquest_plos_%3E1712780278%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1719285071&rft_id=info:pmid/26367392&rft_doaj_id=oai_doaj_org_article_7bf6373919b94469af271122320069f5&rfr_iscdi=true |