The J Domain of Sacsin Disrupts Intermediate Filament Assembly
Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured...
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| Veröffentlicht in: | International journal of molecular sciences 2022-12, Vol.23 (24), p.15742 |
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| creator | Dabbaghizadeh, Afrooz Paré, Alexandre Cheng-Boivin, Zacharie Dagher, Robin Minotti, Sandra Dicaire, Marie-Josée Brais, Bernard Young, Jason C Durham, Heather D Gentil, Benoit J |
| description | Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured
neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured
motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured
fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells. |
| doi_str_mv | 10.3390/ijms232415742 |
| format | Article |
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neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured
motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured
fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms232415742</identifier><identifier>PMID: 36555380</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Ataxia ; Autophagy ; Dismantling ; Fibroblasts ; Filaments ; Heat shock proteins ; Heat-Shock Proteins - metabolism ; Homeostasis ; Hsp40 protein ; Hsp70 protein ; Humans ; Intermediate filaments ; Intermediate Filaments - metabolism ; Motor neurons ; Motor Neurons - metabolism ; Muscle Spasticity - genetics ; Muscle Spasticity - metabolism ; Mutation ; Myc protein ; Neurofilaments ; Neurons ; Patients ; Peptides ; Proteins ; Quality control ; Sedimentation & deposition ; Vimentin ; Vimentin - genetics ; Vimentin - metabolism</subject><ispartof>International journal of molecular sciences, 2022-12, Vol.23 (24), p.15742</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-fe55e02eaacc0cf88eb43295fe8b00fdf00525e86a5d55c02eb4c6d2c72927393</citedby><cites>FETCH-LOGICAL-c415t-fe55e02eaacc0cf88eb43295fe8b00fdf00525e86a5d55c02eb4c6d2c72927393</cites><orcidid>0000-0001-8692-6055 ; 0000-0003-2022-1890</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/PMC9779362/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779362/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36555380$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dabbaghizadeh, Afrooz</creatorcontrib><creatorcontrib>Paré, Alexandre</creatorcontrib><creatorcontrib>Cheng-Boivin, Zacharie</creatorcontrib><creatorcontrib>Dagher, Robin</creatorcontrib><creatorcontrib>Minotti, Sandra</creatorcontrib><creatorcontrib>Dicaire, Marie-Josée</creatorcontrib><creatorcontrib>Brais, Bernard</creatorcontrib><creatorcontrib>Young, Jason C</creatorcontrib><creatorcontrib>Durham, Heather D</creatorcontrib><creatorcontrib>Gentil, Benoit J</creatorcontrib><title>The J Domain of Sacsin Disrupts Intermediate Filament Assembly</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured
neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured
motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured
fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.</description><subject>Ataxia</subject><subject>Autophagy</subject><subject>Dismantling</subject><subject>Fibroblasts</subject><subject>Filaments</subject><subject>Heat shock proteins</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Homeostasis</subject><subject>Hsp40 protein</subject><subject>Hsp70 protein</subject><subject>Humans</subject><subject>Intermediate filaments</subject><subject>Intermediate Filaments - metabolism</subject><subject>Motor neurons</subject><subject>Motor Neurons - metabolism</subject><subject>Muscle Spasticity - genetics</subject><subject>Muscle Spasticity - metabolism</subject><subject>Mutation</subject><subject>Myc protein</subject><subject>Neurofilaments</subject><subject>Neurons</subject><subject>Patients</subject><subject>Peptides</subject><subject>Proteins</subject><subject>Quality control</subject><subject>Sedimentation & deposition</subject><subject>Vimentin</subject><subject>Vimentin - genetics</subject><subject>Vimentin - metabolism</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1LAzEQxYMotlaPXmXBi5fVbLLZ7F4KpbVaKXiwnkM2O7Ep-1GTXaH_vamtxXqagfnx5j0eQtcRvqc0ww9mVTlCSRwxHpMT1I9iQkKME376Z--hC-dWGHuQZeeoRxPGGE1xHw0XSwhegklTSVMHjQ7epHJ-mxhnu3Xrglndgq2gMLKFYGpKWUHdBiPnoMrLzSU607J0cLWfA_Q-fVyMn8P569NsPJqHyhtrQw2MASYgpVJY6TSFPKYkYxrSHGNdaIwZYZAmkhWMKU_msUoKojjJCKcZHaDhTnfd5d6M8h6sLMXamkrajWikEceX2izFR_MlMs4zmhAvcLcXsM1nB64VlXEKylLW0HROEM7SCOPs59ftP3TVdLb28bZUwmkSx6mnwh2lbOOcBX0wE2GxbUYcNeP5m78JDvRvFfQbeayJog</recordid><startdate>20221212</startdate><enddate>20221212</enddate><creator>Dabbaghizadeh, Afrooz</creator><creator>Paré, Alexandre</creator><creator>Cheng-Boivin, Zacharie</creator><creator>Dagher, Robin</creator><creator>Minotti, Sandra</creator><creator>Dicaire, Marie-Josée</creator><creator>Brais, Bernard</creator><creator>Young, Jason C</creator><creator>Durham, Heather D</creator><creator>Gentil, Benoit J</creator><general>MDPI AG</general><general>MDPI</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8692-6055</orcidid><orcidid>https://orcid.org/0000-0003-2022-1890</orcidid></search><sort><creationdate>20221212</creationdate><title>The J Domain of Sacsin Disrupts Intermediate Filament Assembly</title><author>Dabbaghizadeh, Afrooz ; 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A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured
neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured
motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured
fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36555380</pmid><doi>10.3390/ijms232415742</doi><orcidid>https://orcid.org/0000-0001-8692-6055</orcidid><orcidid>https://orcid.org/0000-0003-2022-1890</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Ataxia Autophagy Dismantling Fibroblasts Filaments Heat shock proteins Heat-Shock Proteins - metabolism Homeostasis Hsp40 protein Hsp70 protein Humans Intermediate filaments Intermediate Filaments - metabolism Motor neurons Motor Neurons - metabolism Muscle Spasticity - genetics Muscle Spasticity - metabolism Mutation Myc protein Neurofilaments Neurons Patients Peptides Proteins Quality control Sedimentation & deposition Vimentin Vimentin - genetics Vimentin - metabolism |
| title | The J Domain of Sacsin Disrupts Intermediate Filament Assembly |
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