C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins
Zhang et al . show that the poly(GA) proteins produced in patients with C9ORF72 repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in...
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| Veröffentlicht in: | Nature neuroscience 2016-05, Vol.19 (5), p.668-677 |
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| creator | Zhang, Yong-Jie Gendron, Tania F Grima, Jonathan C Sasaguri, Hiroki Jansen-West, Karen Xu, Ya-Fei Katzman, Rebecca B Gass, Jennifer Murray, Melissa E Shinohara, Mitsuru Lin, Wen-Lang Garrett, Aliesha Stankowski, Jeannette N Daughrity, Lillian Tong, Jimei Perkerson, Emilie A Yue, Mei Chew, Jeannie Castanedes-Casey, Monica Kurti, Aishe Wang, Zizhao S Liesinger, Amanda M Baker, Jeremy D Jiang, Jie Lagier-Tourenne, Clotilde Edbauer, Dieter Cleveland, Don W Rademakers, Rosa Boylan, Kevin B Bu, Guojun Link, Christopher D Dickey, Chad A Rothstein, Jeffrey D Dickson, Dennis W Fryer, John D Petrucelli, Leonard |
| description | Zhang
et al
. show that the poly(GA) proteins produced in patients with
C9ORF72
repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.
Neuronal inclusions of poly(GA), a protein unconventionally translated from G
4
C
2
repeat expansions in
C9ORF72
, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in
C9ORF72
expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology. |
| doi_str_mv | 10.1038/nn.4272 |
| format | Article |
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et al
. show that the poly(GA) proteins produced in patients with
C9ORF72
repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.
Neuronal inclusions of poly(GA), a protein unconventionally translated from G
4
C
2
repeat expansions in
C9ORF72
, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in
C9ORF72
expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.</description><identifier>ISSN: 1097-6256</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/nn.4272</identifier><identifier>PMID: 26998601</identifier><identifier>CODEN: NANEFN</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>14/19 ; 631/378 ; 64/60 ; 692/699/375/365 ; 82/1 ; 82/29 ; 82/80 ; 96/35 ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - metabolism ; Amyotrophic Lateral Sclerosis - pathology ; Animal Genetics and Genomics ; Animals ; Atrophy - pathology ; Behavior, Animal ; Behavioral Sciences ; Biological Techniques ; Biomedicine ; Brain - metabolism ; Brain - pathology ; Brain - ultrastructure ; C9orf72 Protein ; Carrier proteins ; Carrier Proteins - metabolism ; Disease ; Disease susceptibility ; DNA-Binding Proteins - metabolism ; Frontotemporal Dementia - metabolism ; Frontotemporal Dementia - pathology ; Gene Expression - genetics ; Genetic aspects ; Guanine Nucleotide Exchange Factors - metabolism ; Humans ; Inclusion Bodies - metabolism ; Inclusion Bodies - ultrastructure ; Medicine ; Mice ; Mutation ; Nerve Degeneration - pathology ; Neurobiology ; Neurodegeneration ; Neurology ; Neurons - metabolism ; Neurons - pathology ; Neuropathology ; Neurosciences ; Open reading frames ; Pathology ; Primary Cell Culture ; Properties ; Proteins ; Proteins - genetics ; Proteins - metabolism ; Proteins - toxicity ; Toxicity ; Ubiquitinated Proteins - metabolism</subject><ispartof>Nature neuroscience, 2016-05, Vol.19 (5), p.668-677</ispartof><rights>Springer Nature America, Inc. 2016</rights><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c564t-8ad55ea19ee52e9c067543b7c336a498c4c5f8ebe3fabcd1b0d141cf7fb4c0d53</citedby><cites>FETCH-LOGICAL-c564t-8ad55ea19ee52e9c067543b7c336a498c4c5f8ebe3fabcd1b0d141cf7fb4c0d53</cites><orcidid>0000-0003-2001-8470 ; 0000-0001-7379-2545 ; 0000-0002-7186-4653 ; 0000-0001-7189-7917</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nn.4272$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nn.4272$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,777,781,882,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26998601$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Yong-Jie</creatorcontrib><creatorcontrib>Gendron, Tania F</creatorcontrib><creatorcontrib>Grima, Jonathan C</creatorcontrib><creatorcontrib>Sasaguri, Hiroki</creatorcontrib><creatorcontrib>Jansen-West, Karen</creatorcontrib><creatorcontrib>Xu, Ya-Fei</creatorcontrib><creatorcontrib>Katzman, Rebecca B</creatorcontrib><creatorcontrib>Gass, Jennifer</creatorcontrib><creatorcontrib>Murray, Melissa E</creatorcontrib><creatorcontrib>Shinohara, Mitsuru</creatorcontrib><creatorcontrib>Lin, Wen-Lang</creatorcontrib><creatorcontrib>Garrett, Aliesha</creatorcontrib><creatorcontrib>Stankowski, Jeannette N</creatorcontrib><creatorcontrib>Daughrity, Lillian</creatorcontrib><creatorcontrib>Tong, Jimei</creatorcontrib><creatorcontrib>Perkerson, Emilie A</creatorcontrib><creatorcontrib>Yue, Mei</creatorcontrib><creatorcontrib>Chew, Jeannie</creatorcontrib><creatorcontrib>Castanedes-Casey, Monica</creatorcontrib><creatorcontrib>Kurti, Aishe</creatorcontrib><creatorcontrib>Wang, Zizhao S</creatorcontrib><creatorcontrib>Liesinger, Amanda M</creatorcontrib><creatorcontrib>Baker, Jeremy D</creatorcontrib><creatorcontrib>Jiang, Jie</creatorcontrib><creatorcontrib>Lagier-Tourenne, Clotilde</creatorcontrib><creatorcontrib>Edbauer, Dieter</creatorcontrib><creatorcontrib>Cleveland, Don W</creatorcontrib><creatorcontrib>Rademakers, Rosa</creatorcontrib><creatorcontrib>Boylan, Kevin B</creatorcontrib><creatorcontrib>Bu, Guojun</creatorcontrib><creatorcontrib>Link, Christopher D</creatorcontrib><creatorcontrib>Dickey, Chad A</creatorcontrib><creatorcontrib>Rothstein, Jeffrey D</creatorcontrib><creatorcontrib>Dickson, Dennis W</creatorcontrib><creatorcontrib>Fryer, John D</creatorcontrib><creatorcontrib>Petrucelli, Leonard</creatorcontrib><title>C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><addtitle>Nat Neurosci</addtitle><description>Zhang
et al
. show that the poly(GA) proteins produced in patients with
C9ORF72
repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.
Neuronal inclusions of poly(GA), a protein unconventionally translated from G
4
C
2
repeat expansions in
C9ORF72
, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in
C9ORF72
expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.</description><subject>14/19</subject><subject>631/378</subject><subject>64/60</subject><subject>692/699/375/365</subject><subject>82/1</subject><subject>82/29</subject><subject>82/80</subject><subject>96/35</subject><subject>Amyotrophic lateral sclerosis</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Amyotrophic Lateral Sclerosis - pathology</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Atrophy - pathology</subject><subject>Behavior, Animal</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedicine</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain - ultrastructure</subject><subject>C9orf72 Protein</subject><subject>Carrier proteins</subject><subject>Carrier Proteins - metabolism</subject><subject>Disease</subject><subject>Disease susceptibility</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Frontotemporal Dementia - metabolism</subject><subject>Frontotemporal Dementia - pathology</subject><subject>Gene Expression - genetics</subject><subject>Genetic aspects</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Humans</subject><subject>Inclusion Bodies - metabolism</subject><subject>Inclusion Bodies - ultrastructure</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mutation</subject><subject>Nerve Degeneration - pathology</subject><subject>Neurobiology</subject><subject>Neurodegeneration</subject><subject>Neurology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neuropathology</subject><subject>Neurosciences</subject><subject>Open reading frames</subject><subject>Pathology</subject><subject>Primary Cell Culture</subject><subject>Properties</subject><subject>Proteins</subject><subject>Proteins - genetics</subject><subject>Proteins - metabolism</subject><subject>Proteins - toxicity</subject><subject>Toxicity</subject><subject>Ubiquitinated Proteins - metabolism</subject><issn>1097-6256</issn><issn>1546-1726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkk1r3DAQhk1padI09B8UQw9NDt7qW_YlsCzNBwQC2-QaIctjV8GWXMku3X9fbZIm2VB0kEbzzCvNy2TZJ4wWGNHym3MLRiR5k-1jzkSBJRFv0xlVshCEi73sQ4x3CCHJy-p9tkdEVZUC4f3sdlVdrU8lyUffb47Olse57roAnZ4g5hF-zRAnCLl2TW6HUduQn68JvY_dbHrwZjP5sddxsCafgnZx9GHKx-AnsC5-zN61uo9w-LgfZDen369X58Xl1dnFanlZGC7YVJS64Rw0rgA4gcogITmjtTSUCs2q0jDD2xJqoK2uTYNr1GCGTSvbmhnUcHqQnTzojnM9QGPApb_0agx20GGjvLZqN-PsT9X534pjWpaCJoGjR4Hg75tWg40G-l478HNUWJayklJiktAvr9A7PweX2ttSjHKBOX-mOt2Dsq716V2zFVVLxqkkBEuRqMV_qLQaSIZ6B61N9zsFxzsFiZngz9TpOUZ18WO9y359YE3wMQZon_zASG3HRjmntmOTyM8v7Xvi_s3Jsz0xpVwH4UXPr7T-AhboyTs</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Zhang, 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poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins</title><author>Zhang, Yong-Jie ; Gendron, Tania F ; Grima, Jonathan C ; Sasaguri, Hiroki ; Jansen-West, Karen ; Xu, Ya-Fei ; Katzman, Rebecca B ; Gass, Jennifer ; Murray, Melissa E ; Shinohara, Mitsuru ; Lin, Wen-Lang ; Garrett, Aliesha ; Stankowski, Jeannette N ; Daughrity, Lillian ; Tong, Jimei ; Perkerson, Emilie A ; Yue, Mei ; Chew, Jeannie ; Castanedes-Casey, Monica ; Kurti, Aishe ; Wang, Zizhao S ; Liesinger, Amanda M ; Baker, Jeremy D ; Jiang, Jie ; Lagier-Tourenne, Clotilde ; Edbauer, Dieter ; Cleveland, Don W ; Rademakers, Rosa ; Boylan, Kevin B ; Bu, Guojun ; Link, Christopher D ; Dickey, Chad A ; Rothstein, Jeffrey D ; Dickson, Dennis W ; Fryer, John D ; Petrucelli, Leonard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c564t-8ad55ea19ee52e9c067543b7c336a498c4c5f8ebe3fabcd1b0d141cf7fb4c0d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>14/19</topic><topic>631/378</topic><topic>64/60</topic><topic>692/699/375/365</topic><topic>82/1</topic><topic>82/29</topic><topic>82/80</topic><topic>96/35</topic><topic>Amyotrophic lateral sclerosis</topic><topic>Amyotrophic Lateral Sclerosis - metabolism</topic><topic>Amyotrophic Lateral Sclerosis - pathology</topic><topic>Animal Genetics and Genomics</topic><topic>Animals</topic><topic>Atrophy - pathology</topic><topic>Behavior, Animal</topic><topic>Behavioral Sciences</topic><topic>Biological Techniques</topic><topic>Biomedicine</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain - ultrastructure</topic><topic>C9orf72 Protein</topic><topic>Carrier proteins</topic><topic>Carrier Proteins - metabolism</topic><topic>Disease</topic><topic>Disease susceptibility</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Frontotemporal Dementia - metabolism</topic><topic>Frontotemporal Dementia - pathology</topic><topic>Gene Expression - genetics</topic><topic>Genetic aspects</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Humans</topic><topic>Inclusion Bodies - metabolism</topic><topic>Inclusion Bodies - ultrastructure</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mutation</topic><topic>Nerve Degeneration - pathology</topic><topic>Neurobiology</topic><topic>Neurodegeneration</topic><topic>Neurology</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neuropathology</topic><topic>Neurosciences</topic><topic>Open reading frames</topic><topic>Pathology</topic><topic>Primary Cell Culture</topic><topic>Properties</topic><topic>Proteins</topic><topic>Proteins - genetics</topic><topic>Proteins - metabolism</topic><topic>Proteins - toxicity</topic><topic>Toxicity</topic><topic>Ubiquitinated Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Yong-Jie</creatorcontrib><creatorcontrib>Gendron, Tania F</creatorcontrib><creatorcontrib>Grima, Jonathan C</creatorcontrib><creatorcontrib>Sasaguri, Hiroki</creatorcontrib><creatorcontrib>Jansen-West, Karen</creatorcontrib><creatorcontrib>Xu, Ya-Fei</creatorcontrib><creatorcontrib>Katzman, Rebecca B</creatorcontrib><creatorcontrib>Gass, Jennifer</creatorcontrib><creatorcontrib>Murray, Melissa E</creatorcontrib><creatorcontrib>Shinohara, Mitsuru</creatorcontrib><creatorcontrib>Lin, Wen-Lang</creatorcontrib><creatorcontrib>Garrett, Aliesha</creatorcontrib><creatorcontrib>Stankowski, Jeannette N</creatorcontrib><creatorcontrib>Daughrity, Lillian</creatorcontrib><creatorcontrib>Tong, Jimei</creatorcontrib><creatorcontrib>Perkerson, Emilie 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Central (Full Participant titles)</collection><jtitle>Nature neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Yong-Jie</au><au>Gendron, Tania F</au><au>Grima, Jonathan C</au><au>Sasaguri, Hiroki</au><au>Jansen-West, Karen</au><au>Xu, Ya-Fei</au><au>Katzman, Rebecca B</au><au>Gass, Jennifer</au><au>Murray, Melissa E</au><au>Shinohara, Mitsuru</au><au>Lin, Wen-Lang</au><au>Garrett, Aliesha</au><au>Stankowski, Jeannette N</au><au>Daughrity, Lillian</au><au>Tong, Jimei</au><au>Perkerson, Emilie A</au><au>Yue, Mei</au><au>Chew, Jeannie</au><au>Castanedes-Casey, Monica</au><au>Kurti, Aishe</au><au>Wang, Zizhao S</au><au>Liesinger, Amanda M</au><au>Baker, Jeremy D</au><au>Jiang, Jie</au><au>Lagier-Tourenne, Clotilde</au><au>Edbauer, Dieter</au><au>Cleveland, Don W</au><au>Rademakers, Rosa</au><au>Boylan, Kevin B</au><au>Bu, Guojun</au><au>Link, Christopher D</au><au>Dickey, Chad A</au><au>Rothstein, Jeffrey D</au><au>Dickson, Dennis W</au><au>Fryer, John D</au><au>Petrucelli, Leonard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins</atitle><jtitle>Nature neuroscience</jtitle><stitle>Nat Neurosci</stitle><addtitle>Nat Neurosci</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>19</volume><issue>5</issue><spage>668</spage><epage>677</epage><pages>668-677</pages><issn>1097-6256</issn><eissn>1546-1726</eissn><coden>NANEFN</coden><abstract>Zhang
et al
. show that the poly(GA) proteins produced in patients with
C9ORF72
repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.
Neuronal inclusions of poly(GA), a protein unconventionally translated from G
4
C
2
repeat expansions in
C9ORF72
, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in
C9ORF72
expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>26998601</pmid><doi>10.1038/nn.4272</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-2001-8470</orcidid><orcidid>https://orcid.org/0000-0001-7379-2545</orcidid><orcidid>https://orcid.org/0000-0002-7186-4653</orcidid><orcidid>https://orcid.org/0000-0001-7189-7917</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-6256 |
| ispartof | Nature neuroscience, 2016-05, Vol.19 (5), p.668-677 |
| issn | 1097-6256 1546-1726 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5138863 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 14/19 631/378 64/60 692/699/375/365 82/1 82/29 82/80 96/35 Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Animal Genetics and Genomics Animals Atrophy - pathology Behavior, Animal Behavioral Sciences Biological Techniques Biomedicine Brain - metabolism Brain - pathology Brain - ultrastructure C9orf72 Protein Carrier proteins Carrier Proteins - metabolism Disease Disease susceptibility DNA-Binding Proteins - metabolism Frontotemporal Dementia - metabolism Frontotemporal Dementia - pathology Gene Expression - genetics Genetic aspects Guanine Nucleotide Exchange Factors - metabolism Humans Inclusion Bodies - metabolism Inclusion Bodies - ultrastructure Medicine Mice Mutation Nerve Degeneration - pathology Neurobiology Neurodegeneration Neurology Neurons - metabolism Neurons - pathology Neuropathology Neurosciences Open reading frames Pathology Primary Cell Culture Properties Proteins Proteins - genetics Proteins - metabolism Proteins - toxicity Toxicity Ubiquitinated Proteins - metabolism |
| title | C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins |
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