Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration
Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB...
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| Veröffentlicht in: | Autophagy 2019-04, Vol.15 (4), p.631-651 |
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| creator | Rusmini, Paola Cortese, Katia Crippa, Valeria Cristofani, Riccardo Cicardi, Maria Elena Ferrari, Veronica Vezzoli, Giulia Tedesco, Barbara Meroni, Marco Messi, Elio Piccolella, Margherita Galbiati, Mariarita Garrè, Massimiliano Morelli, Elena Vaccari, Thomas Poletti, Angelo |
| description | Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). This effect correlated with the calcium-dependent phosphatase PPP3/calcineurin activation, TFEB dephosphorylation and nuclear translocation. Trehalose upregulated genes for the TFEB target and regulator Ppargc1a, lysosomal hydrolases and membrane proteins (Ctsb, Gla, Lamp2a, Mcoln1, Tpp1) and several autophagy-related components (Becn1, Atg10, Atg12, Sqstm1/p62, Map1lc3b, Hspb8 and Bag3) mostly in a PPP3- and TFEB-dependent manner. TFEB silencing counteracted the trehalose pro-degradative activity on misfolded protein causative of motoneuron diseases. Similar effects were exerted by trehalase-resistant trehalose analogs, melibiose and lactulose. Thus, limited lysosomal damage might induce autophagy, perhaps as a compensatory mechanism, a process that is beneficial to counteract neurodegeneration.
Abbreviations: ALS: amyotrophic lateral sclerosis; AR: androgen receptor; ATG: autophagy related; AV: autophagic vacuole; BAG3: BCL2-associated athanogene 3; BECN1: beclin 1, autophagy related; CASA: chaperone-assisted selective autophagy; CTSB: cathepsin b; DAPI: 4ʹ,6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; EGFP: enhanced green fluorescent protein; fALS, familial amyotrophic lateral sclerosis; FRA: filter retardation assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLA: galactosidase, alpha; HD: Huntington disease; hIPSCs: human induced pluripotent stem cells; HSPA8: heat shock protein A8; HSPB8: heat shock protein B8; IF: immunofluorescence analysis; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LGALS3: lectin, galactose binding, soluble 3; LLOMe: L-leucyl-L-leucine methyl ester; LMP: lysosomal membrane permeabilization; Lys: lysosomes; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NDs: neurodegenerative diseases; NSC34: neuroblastoma x spinal cord |
| doi_str_mv | 10.1080/15548627.2018.1535292 |
| format | Article |
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Abbreviations: ALS: amyotrophic lateral sclerosis; AR: androgen receptor; ATG: autophagy related; AV: autophagic vacuole; BAG3: BCL2-associated athanogene 3; BECN1: beclin 1, autophagy related; CASA: chaperone-assisted selective autophagy; CTSB: cathepsin b; DAPI: 4ʹ,6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; EGFP: enhanced green fluorescent protein; fALS, familial amyotrophic lateral sclerosis; FRA: filter retardation assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLA: galactosidase, alpha; HD: Huntington disease; hIPSCs: human induced pluripotent stem cells; HSPA8: heat shock protein A8; HSPB8: heat shock protein B8; IF: immunofluorescence analysis; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LGALS3: lectin, galactose binding, soluble 3; LLOMe: L-leucyl-L-leucine methyl ester; LMP: lysosomal membrane permeabilization; Lys: lysosomes; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NDs: neurodegenerative diseases; NSC34: neuroblastoma x spinal cord 34; PBS: phosphate-buffered saline; PD: Parkinson disease; polyQ: polyglutamine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PPP3CB: protein phosphatase 3, catalytic subunit, beta isoform; RT-qPCR: real-time quantitative polymerase chain reaction; SBMA: spinal and bulbar muscular atrophy; SCAs: spinocerebellar ataxias; siRNA: small interfering RNA; SLC2A8: solute carrier family 2, (facilitated glucose transporter), member 8; smNPCs: small molecules neural progenitors cells; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STED: stimulated emission depletion; STUB1: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TFEB: transcription factor EB; TPP1: tripeptidyl peptidase I; TREH: trehalase (brush-border membrane glycoprotein); WB: western blotting; ZKSCAN3: zinc finger with KRAB and SCAN domains 3</description><identifier>ISSN: 1554-8627</identifier><identifier>EISSN: 1554-8635</identifier><identifier>DOI: 10.1080/15548627.2018.1535292</identifier><identifier>PMID: 30335591</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - drug therapy ; Amyotrophic Lateral Sclerosis - metabolism ; Animals ; Autophagosomes - drug effects ; Autophagosomes - enzymology ; Autophagosomes - metabolism ; autophagy ; Autophagy - drug effects ; Autophagy - genetics ; Autophagy-Related Proteins - genetics ; Autophagy-Related Proteins - metabolism ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; Bulbo-Spinal Atrophy, X-Linked - drug therapy ; Bulbo-Spinal Atrophy, X-Linked - metabolism ; calcineurin ; Calcineurin - genetics ; Calcineurin - metabolism ; Calcium - metabolism ; Cell Differentiation ; Cell Nucleus - metabolism ; Down-Regulation - genetics ; galectin-3 ; Humans ; Induced Pluripotent Stem Cells - enzymology ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - pathology ; Induced Pluripotent Stem Cells - ultrastructure ; lactulose ; lysosomes ; Lysosomes - drug effects ; Lysosomes - enzymology ; Lysosomes - metabolism ; Lysosomes - ultrastructure ; melibiose ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Microtubule-Associated Proteins - metabolism ; motoneuron diseases ; Motor Neurons - enzymology ; Motor Neurons - metabolism ; Motor Neurons - pathology ; Motor Neurons - ultrastructure ; neurodegeneration ; Neuroprotection - drug effects ; Neuroprotection - genetics ; protein quality control ; Research Paper - Basic Science ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Sequestosome-1 Protein - metabolism ; Signal Transduction - drug effects ; Signal Transduction - genetics ; spinal and bulbar muscular atrophy ; TFEB ; trehalose ; Trehalose - analogs & derivatives ; Trehalose - pharmacology ; Unfolded Protein Response - genetics</subject><ispartof>Autophagy, 2019-04, Vol.15 (4), p.631-651</ispartof><rights>2018 Informa UK Limited, trading as Taylor & Francis Group 2018</rights><rights>2018 Informa UK Limited, trading as Taylor & Francis Group 2018 Informa UK Limited, trading as Taylor & Francis Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c494t-d124f422cb50c13099ca4540676af6c72e8a0105f94333bef3168ce257c824b83</citedby><cites>FETCH-LOGICAL-c494t-d124f422cb50c13099ca4540676af6c72e8a0105f94333bef3168ce257c824b83</cites><orcidid>0000-0003-2719-846X ; 0000-0002-6231-7105 ; 0000-0001-6682-4799 ; 0000-0003-3250-5591 ; 0000-0002-8883-0468 ; 0000-0002-7077-3696 ; 0000-0003-2514-9445 ; 0000-0002-9515-1463 ; 0000-0002-3058-5711 ; 0000-0001-9989-0733 ; 0000-0001-9490-303X ; 0000-0001-9218-8933 ; 0000-0003-2032-4179 ; 0000-0002-5130-1116</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526812/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526812/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30335591$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rusmini, Paola</creatorcontrib><creatorcontrib>Cortese, Katia</creatorcontrib><creatorcontrib>Crippa, Valeria</creatorcontrib><creatorcontrib>Cristofani, Riccardo</creatorcontrib><creatorcontrib>Cicardi, Maria Elena</creatorcontrib><creatorcontrib>Ferrari, Veronica</creatorcontrib><creatorcontrib>Vezzoli, Giulia</creatorcontrib><creatorcontrib>Tedesco, Barbara</creatorcontrib><creatorcontrib>Meroni, Marco</creatorcontrib><creatorcontrib>Messi, Elio</creatorcontrib><creatorcontrib>Piccolella, Margherita</creatorcontrib><creatorcontrib>Galbiati, Mariarita</creatorcontrib><creatorcontrib>Garrè, Massimiliano</creatorcontrib><creatorcontrib>Morelli, Elena</creatorcontrib><creatorcontrib>Vaccari, Thomas</creatorcontrib><creatorcontrib>Poletti, Angelo</creatorcontrib><title>Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration</title><title>Autophagy</title><addtitle>Autophagy</addtitle><description>Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). This effect correlated with the calcium-dependent phosphatase PPP3/calcineurin activation, TFEB dephosphorylation and nuclear translocation. Trehalose upregulated genes for the TFEB target and regulator Ppargc1a, lysosomal hydrolases and membrane proteins (Ctsb, Gla, Lamp2a, Mcoln1, Tpp1) and several autophagy-related components (Becn1, Atg10, Atg12, Sqstm1/p62, Map1lc3b, Hspb8 and Bag3) mostly in a PPP3- and TFEB-dependent manner. TFEB silencing counteracted the trehalose pro-degradative activity on misfolded protein causative of motoneuron diseases. Similar effects were exerted by trehalase-resistant trehalose analogs, melibiose and lactulose. Thus, limited lysosomal damage might induce autophagy, perhaps as a compensatory mechanism, a process that is beneficial to counteract neurodegeneration.
Abbreviations: ALS: amyotrophic lateral sclerosis; AR: androgen receptor; ATG: autophagy related; AV: autophagic vacuole; BAG3: BCL2-associated athanogene 3; BECN1: beclin 1, autophagy related; CASA: chaperone-assisted selective autophagy; CTSB: cathepsin b; DAPI: 4ʹ,6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; EGFP: enhanced green fluorescent protein; fALS, familial amyotrophic lateral sclerosis; FRA: filter retardation assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLA: galactosidase, alpha; HD: Huntington disease; hIPSCs: human induced pluripotent stem cells; HSPA8: heat shock protein A8; HSPB8: heat shock protein B8; IF: immunofluorescence analysis; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LGALS3: lectin, galactose binding, soluble 3; LLOMe: L-leucyl-L-leucine methyl ester; LMP: lysosomal membrane permeabilization; Lys: lysosomes; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NDs: neurodegenerative diseases; NSC34: neuroblastoma x spinal cord 34; PBS: phosphate-buffered saline; PD: Parkinson disease; polyQ: polyglutamine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PPP3CB: protein phosphatase 3, catalytic subunit, beta isoform; RT-qPCR: real-time quantitative polymerase chain reaction; SBMA: spinal and bulbar muscular atrophy; SCAs: spinocerebellar ataxias; siRNA: small interfering RNA; SLC2A8: solute carrier family 2, (facilitated glucose transporter), member 8; smNPCs: small molecules neural progenitors cells; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STED: stimulated emission depletion; STUB1: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TFEB: transcription factor EB; TPP1: tripeptidyl peptidase I; TREH: trehalase (brush-border membrane glycoprotein); WB: western blotting; ZKSCAN3: zinc finger with KRAB and SCAN domains 3</description><subject>Amyotrophic lateral sclerosis</subject><subject>Amyotrophic Lateral Sclerosis - drug therapy</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Animals</subject><subject>Autophagosomes - drug effects</subject><subject>Autophagosomes - enzymology</subject><subject>Autophagosomes - metabolism</subject><subject>autophagy</subject><subject>Autophagy - drug effects</subject><subject>Autophagy - genetics</subject><subject>Autophagy-Related Proteins - genetics</subject><subject>Autophagy-Related Proteins - metabolism</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>Bulbo-Spinal Atrophy, X-Linked - drug therapy</subject><subject>Bulbo-Spinal Atrophy, X-Linked - metabolism</subject><subject>calcineurin</subject><subject>Calcineurin - genetics</subject><subject>Calcineurin - metabolism</subject><subject>Calcium - metabolism</subject><subject>Cell Differentiation</subject><subject>Cell Nucleus - metabolism</subject><subject>Down-Regulation - genetics</subject><subject>galectin-3</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - enzymology</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Induced Pluripotent Stem Cells - pathology</subject><subject>Induced Pluripotent Stem Cells - ultrastructure</subject><subject>lactulose</subject><subject>lysosomes</subject><subject>Lysosomes - drug effects</subject><subject>Lysosomes - enzymology</subject><subject>Lysosomes - metabolism</subject><subject>Lysosomes - ultrastructure</subject><subject>melibiose</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>motoneuron diseases</subject><subject>Motor Neurons - enzymology</subject><subject>Motor Neurons - metabolism</subject><subject>Motor Neurons - pathology</subject><subject>Motor Neurons - ultrastructure</subject><subject>neurodegeneration</subject><subject>Neuroprotection - drug effects</subject><subject>Neuroprotection - genetics</subject><subject>protein quality control</subject><subject>Research Paper - Basic Science</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Sequestosome-1 Protein - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>spinal and bulbar muscular atrophy</subject><subject>TFEB</subject><subject>trehalose</subject><subject>Trehalose - analogs & derivatives</subject><subject>Trehalose - pharmacology</subject><subject>Unfolded Protein Response - genetics</subject><issn>1554-8627</issn><issn>1554-8635</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1vEzEQhlcIREvhJ4D2yGWDP3e9FwRULSBV4hLO1sQ7Toy8drB3g_Lv6zRpRC89eTR-3pmRnqp6T8mCEkU-USmFalm3YISqBZVcsp69qC4P_Ua1XL4816y7qN7k_IcQ3qqeva4uOOFcyp5eVutlwg34mLF2YZgN5hrmKW43sN7XOwe13-eY4wi-GXFwMOFQL29vvtVgJreDycVQgvUYB_S5jrZUUww4p9IfcI0B0wP0tnplwWd8d3qvqt-3N8vrH83dr-8_r7_eNUb0YmoGyoQVjJmVJIZy0vcGhBSk7VqwrekYKiCUSNsLzvkKLaetMshkZxQTK8Wvqs_Hudt5VQ42GKYEXm-TGyHtdQSnn_4Et9HruNOtZK2irAz4eBqQ4t8Z86RHlw16DwHjnDUrTMf64qCg8oiaFHNOaM9rKNEHSfpRkj5I0idJJffh_xvPqUcrBfhyBFywMY3wLyY_6An2PiabIBiXNX9-xz072qMx</recordid><startdate>20190403</startdate><enddate>20190403</enddate><creator>Rusmini, Paola</creator><creator>Cortese, Katia</creator><creator>Crippa, Valeria</creator><creator>Cristofani, Riccardo</creator><creator>Cicardi, Maria Elena</creator><creator>Ferrari, Veronica</creator><creator>Vezzoli, Giulia</creator><creator>Tedesco, Barbara</creator><creator>Meroni, Marco</creator><creator>Messi, Elio</creator><creator>Piccolella, Margherita</creator><creator>Galbiati, Mariarita</creator><creator>Garrè, Massimiliano</creator><creator>Morelli, Elena</creator><creator>Vaccari, Thomas</creator><creator>Poletti, Angelo</creator><general>Taylor & Francis</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>5PM</scope><orcidid>https://orcid.org/0000-0003-2719-846X</orcidid><orcidid>https://orcid.org/0000-0002-6231-7105</orcidid><orcidid>https://orcid.org/0000-0001-6682-4799</orcidid><orcidid>https://orcid.org/0000-0003-3250-5591</orcidid><orcidid>https://orcid.org/0000-0002-8883-0468</orcidid><orcidid>https://orcid.org/0000-0002-7077-3696</orcidid><orcidid>https://orcid.org/0000-0003-2514-9445</orcidid><orcidid>https://orcid.org/0000-0002-9515-1463</orcidid><orcidid>https://orcid.org/0000-0002-3058-5711</orcidid><orcidid>https://orcid.org/0000-0001-9989-0733</orcidid><orcidid>https://orcid.org/0000-0001-9490-303X</orcidid><orcidid>https://orcid.org/0000-0001-9218-8933</orcidid><orcidid>https://orcid.org/0000-0003-2032-4179</orcidid><orcidid>https://orcid.org/0000-0002-5130-1116</orcidid></search><sort><creationdate>20190403</creationdate><title>Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration</title><author>Rusmini, Paola ; Cortese, Katia ; Crippa, Valeria ; Cristofani, Riccardo ; Cicardi, Maria Elena ; Ferrari, Veronica ; Vezzoli, Giulia ; Tedesco, Barbara ; Meroni, Marco ; Messi, Elio ; Piccolella, Margherita ; Galbiati, Mariarita ; Garrè, Massimiliano ; Morelli, Elena ; Vaccari, Thomas ; Poletti, Angelo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-d124f422cb50c13099ca4540676af6c72e8a0105f94333bef3168ce257c824b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Amyotrophic lateral sclerosis</topic><topic>Amyotrophic Lateral Sclerosis - drug therapy</topic><topic>Amyotrophic Lateral Sclerosis - metabolism</topic><topic>Animals</topic><topic>Autophagosomes - drug effects</topic><topic>Autophagosomes - enzymology</topic><topic>Autophagosomes - metabolism</topic><topic>autophagy</topic><topic>Autophagy - drug effects</topic><topic>Autophagy - genetics</topic><topic>Autophagy-Related Proteins - genetics</topic><topic>Autophagy-Related Proteins - metabolism</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</topic><topic>Bulbo-Spinal Atrophy, X-Linked - drug therapy</topic><topic>Bulbo-Spinal Atrophy, X-Linked - metabolism</topic><topic>calcineurin</topic><topic>Calcineurin - genetics</topic><topic>Calcineurin - metabolism</topic><topic>Calcium - metabolism</topic><topic>Cell Differentiation</topic><topic>Cell Nucleus - metabolism</topic><topic>Down-Regulation - genetics</topic><topic>galectin-3</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells - enzymology</topic><topic>Induced Pluripotent Stem Cells - metabolism</topic><topic>Induced Pluripotent Stem Cells - pathology</topic><topic>Induced Pluripotent Stem Cells - ultrastructure</topic><topic>lactulose</topic><topic>lysosomes</topic><topic>Lysosomes - drug effects</topic><topic>Lysosomes - enzymology</topic><topic>Lysosomes - metabolism</topic><topic>Lysosomes - ultrastructure</topic><topic>melibiose</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>motoneuron diseases</topic><topic>Motor Neurons - enzymology</topic><topic>Motor Neurons - metabolism</topic><topic>Motor Neurons - pathology</topic><topic>Motor Neurons - ultrastructure</topic><topic>neurodegeneration</topic><topic>Neuroprotection - drug effects</topic><topic>Neuroprotection - genetics</topic><topic>protein quality control</topic><topic>Research Paper - Basic Science</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Sequestosome-1 Protein - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>spinal and bulbar muscular atrophy</topic><topic>TFEB</topic><topic>trehalose</topic><topic>Trehalose - analogs & derivatives</topic><topic>Trehalose - pharmacology</topic><topic>Unfolded Protein Response - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rusmini, Paola</creatorcontrib><creatorcontrib>Cortese, Katia</creatorcontrib><creatorcontrib>Crippa, Valeria</creatorcontrib><creatorcontrib>Cristofani, Riccardo</creatorcontrib><creatorcontrib>Cicardi, Maria Elena</creatorcontrib><creatorcontrib>Ferrari, Veronica</creatorcontrib><creatorcontrib>Vezzoli, Giulia</creatorcontrib><creatorcontrib>Tedesco, Barbara</creatorcontrib><creatorcontrib>Meroni, Marco</creatorcontrib><creatorcontrib>Messi, Elio</creatorcontrib><creatorcontrib>Piccolella, Margherita</creatorcontrib><creatorcontrib>Galbiati, Mariarita</creatorcontrib><creatorcontrib>Garrè, Massimiliano</creatorcontrib><creatorcontrib>Morelli, Elena</creatorcontrib><creatorcontrib>Vaccari, Thomas</creatorcontrib><creatorcontrib>Poletti, Angelo</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>PubMed Central (Full Participant titles)</collection><jtitle>Autophagy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rusmini, Paola</au><au>Cortese, Katia</au><au>Crippa, Valeria</au><au>Cristofani, Riccardo</au><au>Cicardi, Maria Elena</au><au>Ferrari, Veronica</au><au>Vezzoli, Giulia</au><au>Tedesco, Barbara</au><au>Meroni, Marco</au><au>Messi, Elio</au><au>Piccolella, Margherita</au><au>Galbiati, Mariarita</au><au>Garrè, Massimiliano</au><au>Morelli, Elena</au><au>Vaccari, Thomas</au><au>Poletti, Angelo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration</atitle><jtitle>Autophagy</jtitle><addtitle>Autophagy</addtitle><date>2019-04-03</date><risdate>2019</risdate><volume>15</volume><issue>4</issue><spage>631</spage><epage>651</epage><pages>631-651</pages><issn>1554-8627</issn><eissn>1554-8635</eissn><abstract>Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). This effect correlated with the calcium-dependent phosphatase PPP3/calcineurin activation, TFEB dephosphorylation and nuclear translocation. Trehalose upregulated genes for the TFEB target and regulator Ppargc1a, lysosomal hydrolases and membrane proteins (Ctsb, Gla, Lamp2a, Mcoln1, Tpp1) and several autophagy-related components (Becn1, Atg10, Atg12, Sqstm1/p62, Map1lc3b, Hspb8 and Bag3) mostly in a PPP3- and TFEB-dependent manner. TFEB silencing counteracted the trehalose pro-degradative activity on misfolded protein causative of motoneuron diseases. Similar effects were exerted by trehalase-resistant trehalose analogs, melibiose and lactulose. Thus, limited lysosomal damage might induce autophagy, perhaps as a compensatory mechanism, a process that is beneficial to counteract neurodegeneration.
Abbreviations: ALS: amyotrophic lateral sclerosis; AR: androgen receptor; ATG: autophagy related; AV: autophagic vacuole; BAG3: BCL2-associated athanogene 3; BECN1: beclin 1, autophagy related; CASA: chaperone-assisted selective autophagy; CTSB: cathepsin b; DAPI: 4ʹ,6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; EGFP: enhanced green fluorescent protein; fALS, familial amyotrophic lateral sclerosis; FRA: filter retardation assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLA: galactosidase, alpha; HD: Huntington disease; hIPSCs: human induced pluripotent stem cells; HSPA8: heat shock protein A8; HSPB8: heat shock protein B8; IF: immunofluorescence analysis; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LGALS3: lectin, galactose binding, soluble 3; LLOMe: L-leucyl-L-leucine methyl ester; LMP: lysosomal membrane permeabilization; Lys: lysosomes; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NDs: neurodegenerative diseases; NSC34: neuroblastoma x spinal cord 34; PBS: phosphate-buffered saline; PD: Parkinson disease; polyQ: polyglutamine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PPP3CB: protein phosphatase 3, catalytic subunit, beta isoform; RT-qPCR: real-time quantitative polymerase chain reaction; SBMA: spinal and bulbar muscular atrophy; SCAs: spinocerebellar ataxias; siRNA: small interfering RNA; SLC2A8: solute carrier family 2, (facilitated glucose transporter), member 8; smNPCs: small molecules neural progenitors cells; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STED: stimulated emission depletion; STUB1: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TFEB: transcription factor EB; TPP1: tripeptidyl peptidase I; TREH: trehalase (brush-border membrane glycoprotein); WB: western blotting; ZKSCAN3: zinc finger with KRAB and SCAN domains 3</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>30335591</pmid><doi>10.1080/15548627.2018.1535292</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0003-2719-846X</orcidid><orcidid>https://orcid.org/0000-0002-6231-7105</orcidid><orcidid>https://orcid.org/0000-0001-6682-4799</orcidid><orcidid>https://orcid.org/0000-0003-3250-5591</orcidid><orcidid>https://orcid.org/0000-0002-8883-0468</orcidid><orcidid>https://orcid.org/0000-0002-7077-3696</orcidid><orcidid>https://orcid.org/0000-0003-2514-9445</orcidid><orcidid>https://orcid.org/0000-0002-9515-1463</orcidid><orcidid>https://orcid.org/0000-0002-3058-5711</orcidid><orcidid>https://orcid.org/0000-0001-9989-0733</orcidid><orcidid>https://orcid.org/0000-0001-9490-303X</orcidid><orcidid>https://orcid.org/0000-0001-9218-8933</orcidid><orcidid>https://orcid.org/0000-0003-2032-4179</orcidid><orcidid>https://orcid.org/0000-0002-5130-1116</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1554-8627 |
| ispartof | Autophagy, 2019-04, Vol.15 (4), p.631-651 |
| issn | 1554-8627 1554-8635 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2123729108 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - drug therapy Amyotrophic Lateral Sclerosis - metabolism Animals Autophagosomes - drug effects Autophagosomes - enzymology Autophagosomes - metabolism autophagy Autophagy - drug effects Autophagy - genetics Autophagy-Related Proteins - genetics Autophagy-Related Proteins - metabolism Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Bulbo-Spinal Atrophy, X-Linked - drug therapy Bulbo-Spinal Atrophy, X-Linked - metabolism calcineurin Calcineurin - genetics Calcineurin - metabolism Calcium - metabolism Cell Differentiation Cell Nucleus - metabolism Down-Regulation - genetics galectin-3 Humans Induced Pluripotent Stem Cells - enzymology Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Induced Pluripotent Stem Cells - ultrastructure lactulose lysosomes Lysosomes - drug effects Lysosomes - enzymology Lysosomes - metabolism Lysosomes - ultrastructure melibiose Membrane Proteins - genetics Membrane Proteins - metabolism Mice Microtubule-Associated Proteins - metabolism motoneuron diseases Motor Neurons - enzymology Motor Neurons - metabolism Motor Neurons - pathology Motor Neurons - ultrastructure neurodegeneration Neuroprotection - drug effects Neuroprotection - genetics protein quality control Research Paper - Basic Science RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Sequestosome-1 Protein - metabolism Signal Transduction - drug effects Signal Transduction - genetics spinal and bulbar muscular atrophy TFEB trehalose Trehalose - analogs & derivatives Trehalose - pharmacology Unfolded Protein Response - genetics |
| title | Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration |
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