Genetic and Chemical Activation of TFEB Mediates Clearance of Aggregated α-Synuclein
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{"title"=>"Genetic and chemical activation of TFEB mediates clearance of aggregated α-synuclein", "type"=>"journal", "authors"=>[{"first_name"=>"Kiri", "last_name"=>"Kilpatrick", "scopus_author_id"=>"55340446800"}, {"first_name"=>"Yimeng", "last_name"=>"Zeng", "scopus_author_id"=>"56571821800"}, {"first_name"=>"Tommy", "last_name"=>"Hancock", "scopus_author_id"=>"55800351900"}, {"first_name"=>"Laura", "last_name"=>"Segatori", "scopus_author_id"=>"8870626000"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"603271729", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0120819", "scopus"=>"2-s2.0-84925597891", "pmid"=>"25790376", "sgr"=>"84925597891"}, "id"=>"da0e44cb-3c30-36ef-b978-4bd937acb339", "abstract"=>"Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of α-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated α-syn by inducing autophagic clearance of α-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-β-cyclodextrin promotes autophagic clearance of aggregated α-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of α-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of α-syn aggregates.", "link"=>"http://www.mendeley.com/research/genetic-chemical-activation-tfeb-mediates-clearance-aggregated-%CE%B1synuclein", "reader_count"=>52, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>2, "Student > Master"=>7, "Other"=>2, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>2, "Student > Master"=>7, "Other"=>2, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>6, "Biochemistry, Genetics and Molecular Biology"=>8, "Materials Science"=>1, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>19, "Neuroscience"=>9, "Chemical Engineering"=>1, "Psychology"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>6}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>9}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Chemical Engineering"=>{"Chemical Engineering"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Finland"=>1, "Russia"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1961947"], "description"=>"<p><b>a)</b> Relative mRNA expression levels of representative genes of the autophagy pathway in H4/α-syn-GFP cells treated with HPβCD (1 mM) for 24 h. <i>MAPLC3</i>, <i>SQSTM1</i>, <i>BECN1</i>, and <i>UVRAG</i> mRNA expression levels were obtained by qRT-PCR and calculated as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120819#pone.0120819.g002\" target=\"_blank\">Fig. 2C</a> (p < 0.05). <b>b)</b> Western blot analyses of LC3 isoforms and GAPDH (used as loading control) in H4/α-syn-GFP cells treated with HPβCD (1 mM) for 24 h and quantification of LC3-II bands. Band intensities were quantified with NIH ImageJ software and corrected by GAPDH band intensities (p < 0.05) <b>c)</b> Immunofluorescence microscopy analysis of LC3 and LAMP2 in H4/α-syn-GFP cells treated with HPβCD (1 mM) for 24 h. Colocalization of LC3 (red, column 1) and LAMP2 (blue, column 2) is shown in purple (column 3). Representative images are reported. Scale bars represent 20 μm. <b>d)</b> Quantification of LC3-LAMP2 colocalization was calculated using randomly selected images containing 30–50 cells obtained from three independent experiments (p < 0.001). <b>e)</b> Fluorescence microscopy analyses of H4/α-syn-GFP cells untreated or treated with HPβCD (1 mM) and/or bafilomycin (100 nM) for 24 h. Images of α-syn-GFP fluorescence (green, column 1) and aggregates, detected using the ProteoStat dye (red, column 2), were merged (column 3) and analyzed using NIH ImageJ software. Representative images are reported. Scale bar represents 20 μm. f) Total protein aggregation in H4/α-syn-GFP cells untreated or treated with HPβCD (1 mM) and/or bafilomycin (100 nM) for 24 h. Total protein aggregation was quantified by measuring binding of the ProteoStat aggregation dye by flow cytometry. The APF was calculated as described in the Methods. Data are reported as mean ± SD (n ≥ 3; p < 0.05).</p>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343596, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120819.g005", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HP_946_CD_treatment_enhances_autophagic_clearance_of_945_syn_aggregates_in_H4_945_syn_GFP_cells_/1343596", "title"=>"HPβCD treatment enhances autophagic clearance of α-syn aggregates in H4/α-syn-GFP cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-19 03:43:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1961943"], "description"=>"<p><b>a)</b> Fluorescence microscopy analyses of H4/α-syn-GFP cells treated with HPβCD (1 mM) for 24 h with or without <i>TFEB</i> siRNA. Images of α-syn-GFP fluorescence (green, column 1) and aggregates, detected using the ProteoStat dye (red, column 2), were merged (column 3) and analyzed using NIH ImageJ software. Representative images are reported. Scale bar represents 20 μm. <b>b)</b> Total protein aggregation in H4/α-syn-GFP cells treated with control siRNA or <i>TFEB</i> siRNA for 48 h and with or without HPβCD (1 mM) for 24 h. Total protein aggregation was quantified by measuring binding of the ProteoStat dye by flow cytometry. The aggregation propensity factor (APF) was calculated as described in the Methods. Data are reported as mean ± SD (n ≥ 3; p<0.05). <b>c)</b> Western blot analyses of α-syn in Triton X-100 soluble and insoluble fraction of H4/α-syn-GFP cells treated with HPβCD (1mM, 3mM and 5mM).</p>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343592, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120819.g003", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HP_946_CD_treatment_results_in_clearance_of_945_syn_aggregates_/1343592", "title"=>"HPβCD treatment results in clearance of α-syn aggregates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-19 03:43:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1961941"], "description"=>"<p>a) Immunofluorescence microscopy analyses of LC3 and LAMP2 in H4/α-syn-GFP cells transduced to express TFEB-3xFLAG. Colocalization of LC3 (red, column 1) and LAMP2 (blue, column 2) is shown in purple (column 3). Representative images are reported. Scale bar represents 20 μm. <b>b)</b> Quantification of LC3- LAMP2 colocalization was calculated using randomly selected images containing 30–50 cells obtained from three independent experiments (p < 0.001). <b>c)</b> Relative mRNA expression levels of representative genes involved in the autophagy pathway in H4/α-syn-GFP cells transduced to overexpress TFEB. <i>MAPLC3</i>, <i>SQSTM1</i>, <i>BECN1</i>, and <i>UVRAG</i> mRNA expression levels were obtained by qRT-PCR, corrected for the expression of the housekeeping genes <i>GAPDH</i> and <i>ACTB</i>, and normalized to those of untreated cells (dashed line). Data are reported as mean ± SD (n ≥ 3; p < 0.05, *p < 0.01). <b>d)</b> Total protein aggregation in H4/α-syn-GFP cells transduced to express TFEB-3xFLAG and treated with bafilomycin (100 nM). Total protein aggregation was quantified by measuring binding of the ProteoStat dye by flow cytometry. The APF was calculated as described in the Methods. Data are reported as mean ± SD (n ≥ 3; p < 0.05).</p>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343590, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120819.g002", "stats"=>{"downloads"=>2, "page_views"=>64, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TFEB_mediates_reduction_of_945_syn_aggregates_by_inducing_autophagic_clearance_/1343590", "title"=>"TFEB mediates reduction of α-syn aggregates by inducing autophagic clearance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-19 03:43:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1961949"], "description"=>"<p><b>a)</b> Immunofluorescence microscopy analyses of TFEB subcellular localization in H4/α-syn-GFP cells untreated or treated with HPβCD (1 mM) or HPβCD–cholesterol complexes (1 mM) for 24 h. TFEB nuclear localization was monitored using a FLAG-specific antibody and DAPI nuclear stain. Colocalization of DAPI (blue, column 1) and TFEB (red, column 2) is shown in purple (column 3). Representative images are reported. Scale bar represents 10 μm. <b>b)</b> Fluorescence microscopy analyses of H4/α-syn-GFP cells untreated or treated with HPβCD (1 mM) or HPβCD–cholesterol complex (1 mM) for 24 h. Images of α-syn-GFP fluorescence (green, column 1) and aggregates, detected using the ProteoStat dye (red, column 2), were merged (column 3) and analyzed using NIH ImageJ software. Representative images are reported. Scale bar represents 20 μm.</p>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343598, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120819.g006", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HP_946_CD_mediated_clearance_of_945_syn_aggregates_does_not_depend_on_the_ability_of_HP_946_CD_to_alter_cholesterol_levels_/1343598", "title"=>"HPβCD-mediated clearance of α-syn aggregates does not depend on the ability of HPβCD to alter cholesterol levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-19 03:43:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1961945"], "description"=>"<p><b>a-b)</b> Immunofluorescence microscopy analysis of TFEB subcellular localization in H4/α-syn-GFP cells treated with HPβCD (1 mM). TFEB nuclear localization was monitored using a TFEB-specific antibody and DAPI nuclear stain. Colocalization of DAPI (blue, row 1) and TFEB (red, row 2) is shown in purple (row 3). Scale bar represents 10 μm. <b>c)</b> Percentage of HPβCD-treated cells presenting TFEB nuclear localization. Representative fields containing 50–100 cells were analyzed (p < 0.05). <b>d)</b> Relative mRNA expression levels of representative CLEAR network genes in H4/α-syn-GFP cells treated with HPβCD (1 mM) for 24 h. <i>GBA</i>, <i>HEXA</i>, and <i>LAMP1</i> mRNA expression levels were obtained by qRT-PCR and calculated as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120819#pone.0120819.g002\" target=\"_blank\">Fig. 2C</a>. Data are reported as mean ± SD (n ≥ 3; p < 0.01).</p>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343594, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120819.g004", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HP_946_CD_treatment_induces_activation_of_TFEB_in_H4_945_syn_GFP_cells_/1343594", "title"=>"HPβCD treatment induces activation of TFEB in H4/α-syn-GFP cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-19 03:43:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1961959", "https://ndownloader.figshare.com/files/1961960", "https://ndownloader.figshare.com/files/1961961", "https://ndownloader.figshare.com/files/1961962", "https://ndownloader.figshare.com/files/1961963"], "description"=>"<div><p>Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson’s disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of α-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated α-syn by inducing autophagic clearance of α-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-β-cyclodextrin promotes autophagic clearance of aggregated α-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of α-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of α-syn aggregates.</p></div>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343606, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0120819.s001", "https://dx.doi.org/10.1371/journal.pone.0120819.s002", "https://dx.doi.org/10.1371/journal.pone.0120819.s003", "https://dx.doi.org/10.1371/journal.pone.0120819.s004", "https://dx.doi.org/10.1371/journal.pone.0120819.s005"], "stats"=>{"downloads"=>12, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_and_Chemical_Activation_of_TFEB_Mediates_Clearance_of_Aggregated_945_Synuclein_/1343606", "title"=>"Genetic and Chemical Activation of TFEB Mediates Clearance of Aggregated α-Synuclein", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-03-19 03:43:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1961939"], "description"=>"<p><b>a)</b> Fluorescence microscopy analyses of H4/α-syn-GFP cells transduced to express TFEB-3xFLAG or S142A TFEB-3xFLAG. Images of α-syn-GFP fluorescence (green, column 1) and aggregates, detected using the ProteoStat dye (red, column 2), were merged (column 3) and analyzed using NIH ImageJ software. Representative images are reported. Scale bar represents 20 μm. <b>b)</b> Total protein aggregation in H4/α-syn-GFP cells transduced to express TFEB-3xFLAG or S142A TFEB-3xFLAG. Total protein aggregation was quantified by measuring binding of the ProteoStat dye by flow cytometry. The aggregation propensity factor (APF) was calculated as described in Methods and normalized to TFEB mRNA expression. Data are reported as mean ± SD (n ≥ 3; p < 0.01). <b>c)</b> Fluorescence microscopy analyses of H4/α-syn-GFP cells treated with control siRNA or <i>TFEB</i> siRNA. Images were analyzed as described in (a). Representative images are reported. Scale bar represents 20 μm. <b>d)</b> Total protein aggregation in H4/α-syn-GFP treated with control siRNA or <i>TFEB</i> siRNA. Total protein aggregation was quantified as described in (b). Data are reported as mean ± SD (n ≥ 3; p < 0.01). e) Immunofluorescence microscopy analyses of TFEB subcellular localization in H4/α-syn-GFP cells transduced to express TFEB-3xFLAG or S142A TFEB-3xFLAG. TFEB nuclear localization was monitored using a FLAG-specific antibody and DAPI nuclear stain. Colocalization of DAPI (blue, column 1) and TFEB-3xFLAG (red, column 2) is shown in purple (column 3). Representative images are reported. Scale bar represents 10 μm. <b>f)</b> Percentage of cells transduced as described in (e) presenting TFEB nuclear localization. Representative fields containing 50–100 cells were analyzed (p < 0.05).</p>", "links"=>[], "tags"=>["TFEB Mediates Clearance", "TFEB modulates autophagic clearance", "intracellular protein degradation systems", "pd", "syn", "transcription factor EB", "autophagic clearance"], "article_id"=>1343588, "categories"=>["Biological Sciences"], "users"=>["Kiri Kilpatrick", "Yimeng Zeng", "Tommy Hancock", "Laura Segatori"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0120819.g001", "stats"=>{"downloads"=>8, "page_views"=>149, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TFEB_overexpression_results_in_reduced_accumulation_of_945_syn_aggregates_/1343588", "title"=>"TFEB overexpression results in reduced accumulation of α-syn aggregates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-19 03:43:45"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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