Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1
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{"title"=>"Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1", "type"=>"journal", "authors"=>[{"first_name"=>"Amber L.", "last_name"=>"Southwell", "scopus_author_id"=>"8160402000"}, {"first_name"=>"Charles W.", "last_name"=>"Bugg", "scopus_author_id"=>"25421289800"}, {"first_name"=>"Linda S.", "last_name"=>"Kaltenbach", "scopus_author_id"=>"55748184800"}, {"first_name"=>"Denise", "last_name"=>"Dunn", "scopus_author_id"=>"25421514200"}, {"first_name"=>"Stefanie", "last_name"=>"Butland", "scopus_author_id"=>"6506584846"}, {"first_name"=>"Andreas", "last_name"=>"Weiss", "scopus_author_id"=>"15021604600"}, {"first_name"=>"Paolo", "last_name"=>"Paganetti", "scopus_author_id"=>"6701854718"}, {"first_name"=>"Donald C.", "last_name"=>"Lo", "scopus_author_id"=>"7102171624"}, {"first_name"=>"Paul H.", "last_name"=>"Patterson", "scopus_author_id"=>"7201502335"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"79551645514", "pmid"=>"21304966", "doi"=>"10.1371/journal.pone.0016676", "pui"=>"361218404", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "scopus"=>"2-s2.0-79551645514"}, "id"=>"3c03118d-8f93-3307-8ebf-52b0b36aa715", "abstract"=>"BACKGROUND: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V(L)12.3, turnover of soluble mHDx-1 in living cells is blocked.\\n\\nCONCLUSIONS/SIGNIFICANCE: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications.", "link"=>"http://www.mendeley.com/research/perturbation-intrabodies-reveals-calpain-cleavage-required-degradation-huntingtin-exon-1", "reader_count"=>28, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>3, "Student > Master"=>3, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>3, "Student > Master"=>3, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>3, "Neuroscience"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Neuroscience"=>{"Neuroscience"=>5}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Austria"=>1, "Germany"=>1, "India"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/801867"], "description"=>"<p>HEK 293 cells were co-transfected with mHDx-1 and iAb in the presence of inhibitors of proteolysis or DMSO vehicle. mHDx-1 protein levels in transfected cell lysates was compared by (A, B) Western blotting and (C) densitometry. There is less mHDx-1 protein in the Happ1 transfected cells as compared to the V<sub>L</sub>12.3 transfected cells in the presence of vehicle, Lactacystin, epoxomicin, 3-MA or caspase inhibitor 1. Happ1-mediated reduction of mHDx-1 levels is blocked by bafilomycin A1 or calpain inhibitor 1 to the same level as mHDx-1 lacking the Happ1 binding site. * = p<.05, N = 4.</p>", "links"=>[], "tags"=>["mhdx-1", "levels"], "article_id"=>472230, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g002", "stats"=>{"downloads"=>5, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Happ1_mediated_reduction_of_mHDx_1_protein_levels_is_calpain_dependent_/472230", "title"=>"Happ1-mediated reduction of mHDx-1 protein levels is calpain-dependent.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:37:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/801742"], "description"=>"<p>mHDx-1 was immunoprecipitated from the lysates of HEK 293 cells co-transfected with mHDx-1 and iAb. (A) Lysates and IPs were Western blotted for Htt and ubiquitin. (B) The ratio of immunoprecipitated Htt (total mHDx-1) to immunoprecipitated ubiquitin (ubiquitinated mHDx-1) was compared. There are no iAb specific effects on this ratio. N = 3.</p>", "links"=>[], "tags"=>["ubiquitination"], "article_id"=>472102, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Happ1_does_not_increase_ubiquitination_of_mHDx_1_/472102", "title"=>"Happ1 does not increase ubiquitination of mHDx-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:35:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/802027"], "description"=>"<p>ST14A cells were co-transfected with mHDx-1-SNAP alone or with iAb in the presence of inhibitors of proteolytic processing or DMSO vehicle. To measure Htt turnover, mHDx-1 protein was labeled 24 Hrs post transfection and cultures were incubated for an additional 24 Hrs. (A) Immunofluorescent images showing labeled mHDx-1 (B) The mean cell intensity of label at 24 Hrs vs. 48 Hrs was used to determine the percentage of mHDx-1 labeled at 24 Hrs that still remained at 48 Hrs. In the presence of epoxomicin or 3M-A there is no change in Happ1-enhanced mHDx-1 turnover as compared to in the presence of DMSO. In the presence of bafilomycin A1 or calpain inhibitor 1, mHDx-1 turnover is not increased by Happ1. * = p<.05, ** = p<.01, N = 3.</p>", "links"=>[], "tags"=>["mhdx-1", "turnover"], "article_id"=>472391, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Happ1_enhanced_mHDx_1_turnover_is_calpain_dependent_/472391", "title"=>"Happ1-enhanced mHDx-1 turnover is calpain-dependent.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:39:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/802364"], "description"=>"<p>Three AA stepped 14-mer peptides were spotted onto nitrocellulose and binding of V<sub>L</sub>12.3 was assessed. (A) Peptide table. (B) Dot blot showing binding of peptides 3, 4 and 5 illustrating that V<sub>L</sub>12.3 requires AAs 15-18 at the minimum and 13-20 at the maximum for recognition of Htt.</p>", "links"=>[], "tags"=>["recognizes", "aas", "13-20"], "article_id"=>472719, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_V_L_12_3_recognizes_AAs_13_20_of_HDx_1_/472719", "title"=>"V<sub>L</sub>12.3 recognizes AAs 13-20 of HDx-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:45:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/400816", "https://ndownloader.figshare.com/files/400853"], "description"=>"<div><h3>Background</h3><p>Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD.</p> <h3>Methodology/Principal Findings</h3><p>We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 <em>in vitro</em> yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V<sub>L</sub>12.3, turnover of soluble mHDx-1 in living cells is blocked.</p> <h3>Conclusions/Significance</h3><p>These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications.</p> </div>", "links"=>[], "tags"=>["perturbation", "intrabodies", "reveals", "calpain", "cleavage", "degradation", "huntingtin", "exon"], "article_id"=>139186, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0016676.s001", "https://dx.doi.org/10.1371/journal.pone.0016676.s002"], "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Perturbation_with_Intrabodies_Reveals_That_Calpain_Cleavage_Is_Required_for_Degradation_of_Huntingtin_Exon_1/139186", "title"=>"Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-01-31 02:33:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/802280"], "description"=>"<p>HDx-1 Q46 fused to thioredoxin (mHDx-1-TRX) was incubated with purified calpain 1 <i>in vitro</i>, separated by PAGE and stained with coomassie to assess cleavage. (A) mHDx-1-TRX construct showing known EKMax cleavage sites and predicted calpain 1 cleavage sites. (B) Coomassie stained PAGE gel showing mHDx-1-TRX in lane 1, which appears as a single band. Cleavage by calpain 1 in lane 2 yields 3 smaller bands which correspond to the predicted products after cleavage at AA 8 and AA 15. Cleavage by EKMax in lane 3 yields 3 bands which correspond to the known cleavage sites. The N-terminal fragments generated by EKMax cleavage, which include the entire TRX tag and linker, are smaller than those generated by calpain cleavage indicating that calpain cleavage must occur within HDx-1. Lanes 4 and 5 are calpain 1 alone and EKMax alone respectively.</p>", "links"=>[], "tags"=>["calpain", "cleaves", "hdx-1", "generating", "cleavage", "fragments", "sites", "aa8"], "article_id"=>472631, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g005", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Purified_calpain_1_cleaves_HDx_1_in_vitro_generating_cleavage_fragments_consistent_with_the_predicted_sites_at_AA8_and_AA15_/472631", "title"=>"Purified calpain 1 cleaves HDx-1 <i>in vitro</i> generating cleavage fragments consistent with the predicted sites at AA8 and AA15.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:43:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/802180"], "description"=>"<p>ST14A cells were co-transfected with mHDx-1ΔPRR-SNAP alone or with iAb. HDx-1-SNAP fusion protein was labeled 24 Hrs post transfection, and labeled protein was observed 24 Hrs later. As expected, Happ1 has no effect on aggregation of mHDx-1 lacking the Happ1 binding site. Conversely, V<sub>L</sub>12.3 is still efficient at preventing aggregation of this modified mHDx-1.</p>", "links"=>[], "tags"=>["inhibit", "aggregation"], "article_id"=>472541, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Happ1_does_not_inhibit_aggregation_of_mHDx_1_916_PRR_/472541", "title"=>"Happ1 does not inhibit aggregation of mHDx-1ΔPRR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:42:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/802435"], "description"=>"<p>(A) Organotypic brain slice cultures were co-transfected with mHDx-1 and V<sub>L</sub>12.3 or CV<sub>L</sub>, a control iAb. Soluble mHDx-1 protein level was assessed in lysates collected 1, 2 or 3 days post-transfection by TR-FRET. The level of mHDx-1 protein declines over time in the presence of CV<sub>L</sub>, but not in the presence of V<sub>L</sub>12.3 indicating impaired clearance. (B) Primary striatal and cortical neurons co-cultured with astroglia were transfected with iAb or mHDx-1 plus iAb. Soluble mHDx-1 protein level was assessed in lysates collected 4, 5 or 6 days post-transfection by TR-FRET. At these later time points, there is dramatically more mHDx-1 protein in the presence of V<sub>L</sub>12.3 as compared to CV<sub>L</sub>.</p>", "links"=>[], "tags"=>["binding", "prevents", "turnover"], "article_id"=>472799, "categories"=>["Neuroscience", "Genetics"], "users"=>["Amber L. Southwell", "Charles W. Bugg", "Linda S. Kaltenbach", "Denise Dunn", "Stefanie Butland", "Andreas Weiss", "Paolo Paganetti", "Donald C. Lo", "Paul H. Patterson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0016676.g007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_V_L_12_3_binding_prevents_turnover_of_HDx_1_/472799", "title"=>"V<sub>L</sub>12.3 binding prevents turnover of HDx-1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-01-31 00:46:39"}

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Relative Metric

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