Late-Onset of Spinal Neurodegeneration in Knock-In Mice Expressing a Mutant BiP
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{"title"=>"Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BIP", "type"=>"journal", "authors"=>[{"first_name"=>"Hisayo", "last_name"=>"Jin", "scopus_author_id"=>"23097598200"}, {"first_name"=>"Naoya", "last_name"=>"Mimura", "scopus_author_id"=>"55799037800"}, {"first_name"=>"Makiko", "last_name"=>"Kashio", "scopus_author_id"=>"57191286403"}, {"first_name"=>"Haruhiko", "last_name"=>"Koseki", "scopus_author_id"=>"7005219774"}, {"first_name"=>"Tomohiko", "last_name"=>"Aoe", "scopus_author_id"=>"7004918780"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84911925193", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "scopus"=>"2-s2.0-84911925193", "pui"=>"600550392", "pmid"=>"25405877", "doi"=>"10.1371/journal.pone.0112837", "issn"=>"19326203"}, "id"=>"68e0a288-7155-363f-9c83-4991d188e98e", "abstract"=>"Most human neurodegenerative diseases are sporadic, and appear later in life. While the underlying mechanisms of the progression of those diseases are still unclear, investigations into the familial forms of comparable diseases suggest that endoplasmic reticulum (ER) stress is involved in the pathogenesis. Binding immunoglobulin protein (BiP) is an ER chaperone that is central to ER function. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence in order to evaluate the effect of a functional defect in an ER chaperone in multi-cellular organisms. Here we report that heterozygous mutant BiP mice revealed motor disabilities in aging. We found a degeneration of some motoneurons in the spinal cord accompanied by accumulations of ubiquitinated proteins. The defect in retrieval of BiP by the KDEL receptor leads to impaired activities in quality control and autophagy, suggesting that functional defects in the ER chaperones may contribute to the late onset of neurodegenerative diseases.", "link"=>"http://www.mendeley.com/research/lateonset-spinal-neurodegeneration-knockin-mice-expressing-mutant-bip", "reader_count"=>17, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>2, "Student > Master"=>3, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>2, "Student > Master"=>3, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Mathematics"=>1, "Agricultural and Biological Sciences"=>8, "Medicine and Dentistry"=>1, "Neuroscience"=>3, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Neuroscience"=>{"Neuroscience"=>3}, "Social Sciences"=>{"Social Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1798649"], "description"=>"<p>(A) Kaplan-Meier plots demonstrate that the heterozygous mutant BiP mice (Bm/+, n = 80) live as long as the wild-type mice (+/+, n = 45). (B) Some of the mutant BiP mice displayed paralysis and tremors after they were more than one year old. Heterozygous mutant BiP mice (Bm/+, n = 104) and wild type mice (n = 50) more than 10 months old were observed. No sign of weakness; +/+ 46/50, Bm/+ 73/104, tremor; +/+ 0/50, Bm/+ 9/104, paresis of one hindlimb; +/+ 4/50, Bm/+ 9/104, paralysis of one or both hindlimbs; +/+ 0/50, Bm/+ 15/104. To compare values between two groups, Chi-square and Fisher's exact test was done. Statistical significance was found. P value is 0.0033. (C) A seventeen month-old mutant BiP mouse displayed paralysis and loss of righting reflex. (D) A seventeen month-old mutant BiP mouse displayed paralysis (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0112837#pone.0112837.s001\" target=\"_blank\">Video S1</a>).</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245229, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g001", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_mutant_BiP_mice_revealed_motor_disabilities_in_aging_/1245229", "title"=>"The mutant BiP mice revealed motor disabilities in aging.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798650"], "description"=>"<p>(A) Motoneurons stained by an anti-choline acetyltransferase antibody (red) at the anterior horn in the spinal cord of both a 6 month-old wild type (+/+, 6 m) and a 6 month-old mutant BiP mouse (Bm/+, 6 m) express ER chaperones as well (green). Scale bars, 20 um. (B) The immunoreactivity with an anti-choline acetyltransferase antibody at the anterior horn is reduced in the aged 29 month-old mutant spinal cord (Bm/+, 29 m). Scale bars, 20 um. (C) Large cells at the anterior horn of the aged 29 month-old mutant spinal cord (Bm/+, 29 m) express ER chaperones as well as CHOP. Scale bars, 10 um. The nuclei were stained with Hoechst 33258 (blue, A and C).</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245230, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g002", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Motoneurons_at_the_anterior_horn_of_spinal_cords_of_aged_mutant_BiP_mice_suffer_from_ER_stress_/1245230", "title"=>"Motoneurons at the anterior horn of spinal cords of aged mutant BiP mice suffer from ER stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798651"], "description"=>"<p>(A) TUNEL staining revealed some apoptotic cells at the anterior horn in the spinal cord of a 29 month-old mutant BiP mouse (Bm/+, 29 m). Scale bars, 10 um. (B) The immunoreactivity with an anti-GFAP antibody at the anterior horn is increased in a 17 month-old mutant spinal cord (Bm/+, 17 m). Scale bars, 20 um. GFAP positive cells are counted (five fields in each mouse, GFAP positive cells/the number of nucleus). +/+, 16 m; 33/199, 35/174, 34/192, 40/181, 42/207, Bm/+, 17 m; 42/132, 50/140, 59/147, 39/154, 58/143 +/+, 6 m; 5/143, 4/131, 4/141, 0/95, 0/107. The ratio of GFAP positive cells is significantly higher in the mutant BiP spinal cord (Bm/+, 17 m) compared to that in the wild type (+/+, 16 m) by t test (p value is 0.0009). (C) The aggregations were stained by an anti-ubiquitin antibody in the large cells at the anterior horn of the 29 month-old mutant spinal cord (Bm/+, 29 m, arrowheads). Scale bars, 10 um.</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245231, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g003", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Some_motoneurons_in_the_spinal_cord_revealed_a_degeneration_accompanied_by_accumulations_of_ubiquitinated_proteins_/1245231", "title"=>"Some motoneurons in the spinal cord revealed a degeneration accompanied by accumulations of ubiquitinated proteins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798652"], "description"=>"<p>The aggregations were evaluated by immunofluorescence microscopy with double labeling by using a rabbit anti-SOD1 antibody (red) and a mouse anti-KDEL mAb for the wild type BiP and other ER chaperones (green, +/+, 5 and 26 month-old), or by using a rabbit anti-SOD1 antibody (red) and a mouse anti-HA mAb (15E6) for the mutant BiP (green, Bm/+, 5 and 26 month-old). Scale bars, 10 um. Aggregations were observed in large cells at the anterior horn of a 26-month-old mutant spinal cord (Bm/+, 26 m).</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245232, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Aggregations_were_obvious_in_the_aged_mutant_BiP_mouse_/1245232", "title"=>"Aggregations were obvious in the aged mutant BiP mouse.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798653"], "description"=>"<p>The heterozygous mutant BiP mice and the litter mate wild type mice were anesthetized by pentobarbital, and the brains and spinal cords were removed. They were subjected to Western blot analysis with an anti-KDEL mouse mAb for BiP and GRP94, an anti-HA mouse mAb for mutant BiP, an anti-CHOP rabbit antiserum, and an anti-SOD1 rabbit antiserum.</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245233, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g005", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_expressions_of_chaperones_in_the_mutant_BiP_mice_/1245233", "title"=>"The expressions of chaperones in the mutant BiP mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798654"], "description"=>"<p>(A, B) A fraction of BiP is secreted from the ER under stressed conditions. The postnuclear supernatants (PNS) from HeLa cells with (B) or without (A) treatment by tunicamycin 2.5 ug ml<sup>−1</sup> for 24 h were separated on a continuous sucrose gradient (20% to 50%, fraction 1; top, fraction 12; bottom). An aliquot of each fraction was analyzed by SDS-PAGE. The distributions of GRP94, BiP, Golgi p58 and calnexin were determined by Western blotting. (C) HeLa cells transiently expressing the mutant BiP with the KDEL sequence deleted were collected and homogenized. The PNS from those cells were separated on a continuous sucrose gradient (20% to 50%, fraction 1; top, fraction 12; bottom). An aliquot of each fraction was analyzed by SDS-PAGE. The distributions of the GRP94, myc-tagged mutant BiP, Golgi p58 and calnexin were determined by Western blotting. (D) Wild-type MEFs and BiP MEFs were treated with tunicamycin (2.5 ug ml<sup>−1</sup> for 12, 24 h) or chloroquine (50 uM for 12 h). Cells were subjected to Western blot analysis with an anti-KDEL mouse mAb for BiP, an anti-HA mouse mAb for mutant BiP, an anti-CHOP rabbit antiserum, an anti-LC3A antiserum, and an anti-tubulin mAb.</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245234, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g006", "stats"=>{"downloads"=>2, "page_views"=>83, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lack_of_the_KDEL_sequence_from_BiP_may_lead_to_some_functional_defects_of_the_ER_chaperone_in_quality_control_and_autophagy_/1245234", "title"=>"Lack of the KDEL sequence from BiP may lead to some functional defects of the ER chaperone in quality control and autophagy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798655"], "description"=>"<p>The aggregations by transient expressions of SOD1-GFP were evaluated by immunofluorescence microscopy with labeling by using a rabbit anti-Derlin1 antibody for the ER staining (red) and SOD1-GFP (green) in wild type (+/+) and the homozygous mutant (Bm/Bm) MEF with Hoechst 33342 for nuclear staining. Scale bars, 10 um. Aggregations of SOD1were observed in the mutant BiP MEF as well as in the wild type MEF treated with a proteasome inhibitor, ALLN (10 ug/ml), at 37°C for 12 h.</p>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245235, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837.g007", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Aggregations_were_obvious_in_the_mutant_BiP_MEF_/1245235", "title"=>"Aggregations were obvious in the mutant BiP MEF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-18 02:58:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/1798656"], "description"=>"<div><p>Most human neurodegenerative diseases are sporadic, and appear later in life. While the underlying mechanisms of the progression of those diseases are still unclear, investigations into the familial forms of comparable diseases suggest that endoplasmic reticulum (ER) stress is involved in the pathogenesis. Binding immunoglobulin protein (BiP) is an ER chaperone that is central to ER function. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence in order to evaluate the effect of a functional defect in an ER chaperone in multi-cellular organisms. Here we report that heterozygous mutant BiP mice revealed motor disabilities in aging. We found a degeneration of some motoneurons in the spinal cord accompanied by accumulations of ubiquitinated proteins. The defect in retrieval of BiP by the KDEL receptor leads to impaired activities in quality control and autophagy, suggesting that functional defects in the ER chaperones may contribute to the late onset of neurodegenerative diseases.</p></div>", "links"=>[], "tags"=>["defect", "Binding immunoglobulin protein", "ER chaperone", "bip", "kdel", "retrieval", "Neurodegenerative diseases"], "article_id"=>1245236, "categories"=>["Uncategorised"], "users"=>["Hisayo Jin", "Naoya Mimura", "Makiko Kashio", "Haruhiko Koseki", "Tomohiko Aoe"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0112837", "stats"=>{"downloads"=>3, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Late_Onset_of_Spinal_Neurodegeneration_in_Knock_In_Mice_Expressing_a_Mutant_BiP_/1245236", "title"=>"Late-Onset of Spinal Neurodegeneration in Knock-In Mice Expressing a Mutant BiP", "pos_in_sequence"=>0, "defined_type"=>2, "published_date"=>"2014-11-18 02:58:31"}

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Relative Metric

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