A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease
Abstract We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 ( LRP6 ) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons...
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| Veröffentlicht in: | Neurobiology of aging 2013-06, Vol.34 (6), p.1709.e9-1709.e18 |
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| creator | Alarcón, Marcelo A Medina, Matías A Hu, Qubai Avila, Miguel E Bustos, Bernabé I Pérez-Palma, Eduardo Peralta, Alexis Salazar, Paulina Ugarte, Giorgia D Reyes, Ariel E Martin, George M Opazo, Carlos Moon, Randall T De Ferrari, Giancarlo V |
| description | Abstract We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 ( LRP6 ) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 ( LRP6 Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6 Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6 Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD. |
| doi_str_mv | 10.1016/j.neurobiolaging.2012.11.004 |
| format | Article |
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Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 ( LRP6 Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6 Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6 Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2012.11.004</identifier><identifier>PMID: 23218566</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Aged, 80 and over ; Alternative splicing ; Alternative Splicing - genetics ; Alzheimer Disease - diagnosis ; Alzheimer Disease - genetics ; Alzheimer's disease ; Animals ; Female ; Genetic Association Studies ; HEK293 Cells ; Humans ; Internal Medicine ; Low Density Lipoprotein Receptor-Related Protein-6 - genetics ; LRP6 ; Male ; Mice ; Middle Aged ; Neurology ; Protein Isoforms - genetics ; Wnt Signaling Pathway - genetics ; Wnt/β-catenin signaling</subject><ispartof>Neurobiology of aging, 2013-06, Vol.34 (6), p.1709.e9-1709.e18</ispartof><rights>Elsevier Inc.</rights><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c507t-47110253318a1e759cb02f9a7cb8ac3e97d13658a3703fbf16b61bc02150e553</citedby><cites>FETCH-LOGICAL-c507t-47110253318a1e759cb02f9a7cb8ac3e97d13658a3703fbf16b61bc02150e553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0197458012005702$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23218566$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alarcón, Marcelo A</creatorcontrib><creatorcontrib>Medina, Matías A</creatorcontrib><creatorcontrib>Hu, Qubai</creatorcontrib><creatorcontrib>Avila, Miguel E</creatorcontrib><creatorcontrib>Bustos, Bernabé I</creatorcontrib><creatorcontrib>Pérez-Palma, Eduardo</creatorcontrib><creatorcontrib>Peralta, Alexis</creatorcontrib><creatorcontrib>Salazar, Paulina</creatorcontrib><creatorcontrib>Ugarte, Giorgia D</creatorcontrib><creatorcontrib>Reyes, Ariel E</creatorcontrib><creatorcontrib>Martin, George M</creatorcontrib><creatorcontrib>Opazo, Carlos</creatorcontrib><creatorcontrib>Moon, Randall T</creatorcontrib><creatorcontrib>De Ferrari, Giancarlo V</creatorcontrib><title>A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>Abstract We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 ( LRP6 ) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 ( LRP6 Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6 Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6 Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alternative splicing</subject><subject>Alternative Splicing - genetics</subject><subject>Alzheimer Disease - diagnosis</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Low Density Lipoprotein Receptor-Related Protein-6 - genetics</subject><subject>LRP6</subject><subject>Male</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Neurology</subject><subject>Protein Isoforms - genetics</subject><subject>Wnt Signaling Pathway - genetics</subject><subject>Wnt/β-catenin signaling</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNksFuEzEQhlcIREPhFZAPSHDZMGOv1xsJIUUVBaRKHOjd8nonqYNjB9ubKjwDD82GtEhwoScf_P0zY39TVa8Q5gjYvt3MA40p9i56s3ZhPeeAfI44B2geVTOUsquxWajH1QxwoepGdnBWPct5AwCqUe3T6owLjp1s21n1c8lC3JNnqzHY4mIwnvl4Ww8UsisH5t0u7lIs5AJLZGlXYqoTeVNoYPcXLVtTIGZ8oRRMcXtieeedJbY3yZlQmMvM5Byt-527deWGLf2PG3JbSq8zG1wmk-l59WRlfKYXd-d5dX354friU3315ePni-VVbSWoUjcKEbgUAjuDpOTC9sBXC6Ns3xkraKEGFK3sjFAgVv0K277F3gJHCSSlOK_enMpO838fKRe9ddmS9yZQHLNGyUF02Er-f1TwieS8bR-AompATGNP6LsTalPMOdFK75LbmnTQCPooWW_035L1UbJG1JPkKf7yrtPYb2n4E763OgGXJ4CmT9w7SjpbR8HS4CaHRQ_RPbTT-38KWe-Cs8Z_owPlTRwn3356m85cg_56XLjjviEHkAq4-AVBLtdx</recordid><startdate>20130601</startdate><enddate>20130601</enddate><creator>Alarcón, Marcelo A</creator><creator>Medina, Matías A</creator><creator>Hu, Qubai</creator><creator>Avila, Miguel E</creator><creator>Bustos, Bernabé I</creator><creator>Pérez-Palma, Eduardo</creator><creator>Peralta, Alexis</creator><creator>Salazar, Paulina</creator><creator>Ugarte, Giorgia D</creator><creator>Reyes, Ariel E</creator><creator>Martin, George M</creator><creator>Opazo, Carlos</creator><creator>Moon, Randall T</creator><creator>De Ferrari, Giancarlo V</creator><general>Elsevier Inc</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>7X8</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20130601</creationdate><title>A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease</title><author>Alarcón, Marcelo A ; Medina, Matías A ; Hu, Qubai ; Avila, Miguel E ; Bustos, Bernabé I ; Pérez-Palma, Eduardo ; Peralta, Alexis ; Salazar, Paulina ; Ugarte, Giorgia D ; Reyes, Ariel E ; Martin, George M ; Opazo, Carlos ; Moon, Randall T ; De Ferrari, Giancarlo V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c507t-47110253318a1e759cb02f9a7cb8ac3e97d13658a3703fbf16b61bc02150e553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alternative splicing</topic><topic>Alternative Splicing - genetics</topic><topic>Alzheimer Disease - diagnosis</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer's disease</topic><topic>Animals</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Low Density Lipoprotein Receptor-Related Protein-6 - genetics</topic><topic>LRP6</topic><topic>Male</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Neurology</topic><topic>Protein Isoforms - genetics</topic><topic>Wnt Signaling Pathway - genetics</topic><topic>Wnt/β-catenin signaling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alarcón, Marcelo A</creatorcontrib><creatorcontrib>Medina, Matías A</creatorcontrib><creatorcontrib>Hu, Qubai</creatorcontrib><creatorcontrib>Avila, Miguel E</creatorcontrib><creatorcontrib>Bustos, Bernabé I</creatorcontrib><creatorcontrib>Pérez-Palma, Eduardo</creatorcontrib><creatorcontrib>Peralta, Alexis</creatorcontrib><creatorcontrib>Salazar, Paulina</creatorcontrib><creatorcontrib>Ugarte, Giorgia D</creatorcontrib><creatorcontrib>Reyes, Ariel E</creatorcontrib><creatorcontrib>Martin, George M</creatorcontrib><creatorcontrib>Opazo, Carlos</creatorcontrib><creatorcontrib>Moon, Randall T</creatorcontrib><creatorcontrib>De Ferrari, Giancarlo V</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Neurobiology of aging</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alarcón, Marcelo A</au><au>Medina, Matías A</au><au>Hu, Qubai</au><au>Avila, Miguel E</au><au>Bustos, Bernabé I</au><au>Pérez-Palma, Eduardo</au><au>Peralta, Alexis</au><au>Salazar, Paulina</au><au>Ugarte, Giorgia D</au><au>Reyes, Ariel E</au><au>Martin, George M</au><au>Opazo, Carlos</au><au>Moon, Randall T</au><au>De Ferrari, Giancarlo V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease</atitle><jtitle>Neurobiology of aging</jtitle><addtitle>Neurobiol Aging</addtitle><date>2013-06-01</date><risdate>2013</risdate><volume>34</volume><issue>6</issue><spage>1709.e9</spage><epage>1709.e18</epage><pages>1709.e9-1709.e18</pages><issn>0197-4580</issn><eissn>1558-1497</eissn><abstract>Abstract We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 ( LRP6 ) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 ( LRP6 Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6 Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/β-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6 Δ3 isoform is a novel splice variant, which shows diminished Wnt/β-catenin signaling activity and might have a functional role in individuals with AD.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23218566</pmid><doi>10.1016/j.neurobiolaging.2012.11.004</doi></addata></record> |
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| identifier | ISSN: 0197-4580 |
| ispartof | Neurobiology of aging, 2013-06, Vol.34 (6), p.1709.e9-1709.e18 |
| issn | 0197-4580 1558-1497 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Aged Aged, 80 and over Alternative splicing Alternative Splicing - genetics Alzheimer Disease - diagnosis Alzheimer Disease - genetics Alzheimer's disease Animals Female Genetic Association Studies HEK293 Cells Humans Internal Medicine Low Density Lipoprotein Receptor-Related Protein-6 - genetics LRP6 Male Mice Middle Aged Neurology Protein Isoforms - genetics Wnt Signaling Pathway - genetics Wnt/β-catenin signaling |
| title | A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease |
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