Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB
Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alz...
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creator | Lin, Chun-Yu Wu, Hsiang-En Weng, Eddie Feng-Ju Wu, Hsuan-Cheng Su, Tsung-Ping Wang, Shao-Ming |
description | Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer’s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G
4
C
2
)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G
4
C
2
)
31
-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In
C9orf72
-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G
4
C
2
)
31
-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with
C9orf72
-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G
4
C
2
)
31
-RNA-expressing NSC34 cells. |
doi_str_mv | 10.1007/s12035-023-03885-9 |
format | Article |
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4
C
2
)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G
4
C
2
)
31
-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In
C9orf72
-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G
4
C
2
)
31
-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with
C9orf72
-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G
4
C
2
)
31
-RNA-expressing NSC34 cells.</description><identifier>ISSN: 0893-7648</identifier><identifier>ISSN: 1559-1182</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-023-03885-9</identifier><identifier>PMID: 38180612</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Active Transport, Cell Nucleus - drug effects ; Alzheimer's disease ; Amyotrophic lateral sclerosis ; Animals ; Autophagy ; Autophagy - drug effects ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; Biomedical and Life Sciences ; Biomedicine ; C9orf72 Protein - genetics ; C9orf72 Protein - metabolism ; Cell Biology ; Cell death ; Cell Line ; Cell Nucleus - drug effects ; Cell Nucleus - metabolism ; Dementia disorders ; Fluvoxamine ; Fluvoxamine - pharmacology ; Frontotemporal dementia ; Humans ; Mice ; Neurobiology ; Neurodegenerative diseases ; Neurology ; Neuroprotection ; Neurosciences ; Nuclear transport ; Protein expression ; Receptors, sigma - metabolism ; Ribonucleic acid ; RNA ; RNA transport ; Sigma-1 Receptor</subject><ispartof>Molecular neurobiology, 2024-08, Vol.61 (8), p.5282-5294</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-41cf39d38dfb195b88eb6e5fd911f15059e5908a9e47d71a67520c178d1efa133</citedby><cites>FETCH-LOGICAL-c475t-41cf39d38dfb195b88eb6e5fd911f15059e5908a9e47d71a67520c178d1efa133</cites><orcidid>0000-0003-1479-9100</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-023-03885-9$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-023-03885-9$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38180612$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Chun-Yu</creatorcontrib><creatorcontrib>Wu, Hsiang-En</creatorcontrib><creatorcontrib>Weng, Eddie Feng-Ju</creatorcontrib><creatorcontrib>Wu, Hsuan-Cheng</creatorcontrib><creatorcontrib>Su, Tsung-Ping</creatorcontrib><creatorcontrib>Wang, Shao-Ming</creatorcontrib><title>Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>Mol Neurobiol</addtitle><description>Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer’s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G
4
C
2
)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G
4
C
2
)
31
-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In
C9orf72
-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G
4
C
2
)
31
-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with
C9orf72
-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G
4
C
2
)
31
-RNA-expressing NSC34 cells.</description><subject>Active Transport, Cell Nucleus - drug effects</subject><subject>Alzheimer's disease</subject><subject>Amyotrophic lateral sclerosis</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>C9orf72 Protein - genetics</subject><subject>C9orf72 Protein - metabolism</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell Line</subject><subject>Cell Nucleus - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Dementia disorders</subject><subject>Fluvoxamine</subject><subject>Fluvoxamine - pharmacology</subject><subject>Frontotemporal dementia</subject><subject>Humans</subject><subject>Mice</subject><subject>Neurobiology</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Neuroprotection</subject><subject>Neurosciences</subject><subject>Nuclear transport</subject><subject>Protein expression</subject><subject>Receptors, sigma - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA transport</subject><subject>Sigma-1 Receptor</subject><issn>0893-7648</issn><issn>1559-1182</issn><issn>1559-1182</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0EokvhD3BAlrhwMXjsOLFPqFS7LVL5UFnOlteZpKmSeGsnq-6_x2VL-ThwmsM888688xLyEvhb4Lx6l0BwqRgXknGptWLmEVmAUoYBaPGYLLg2klVloY_Is5SuORcCePWUHEkNmpcgFqRd9fMu3LqhG5EubzFOiX7r2sExuKRToJeY_Iz0ZJ7C9sq1e7rrHP0aBhDAPmHduQlr-nn2PQa_z0zv0tB5uo5uTNsQJxoaul4tPzwnTxrXJ3xxX4_J99VyfXrOLr6cfTw9uWC-qNTECvCNNLXUdbMBozZa46ZE1dQGoAHFlUFluHYGi6quwJWVEtxDpWvAxoGUx-T9QXc7bwasPY5TdL3dxm5wcW-D6-zfnbG7sm3YWQBRmIrzrPDmXiGGmxnTZIcueex7N2KYkxVGaKPKsrhDX_-DXoc5jtmflVxzkx8uVabEgfIxpBSxebgGuL0L0h6CtJm2P4O0Jg-9-tPHw8iv5DIgD0DKrbHF-Hv3f2R_APoYqNA</recordid><startdate>20240801</startdate><enddate>20240801</enddate><creator>Lin, Chun-Yu</creator><creator>Wu, Hsiang-En</creator><creator>Weng, Eddie Feng-Ju</creator><creator>Wu, Hsuan-Cheng</creator><creator>Su, Tsung-Ping</creator><creator>Wang, Shao-Ming</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</scope><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>7QR</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1479-9100</orcidid></search><sort><creationdate>20240801</creationdate><title>Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB</title><author>Lin, Chun-Yu ; Wu, Hsiang-En ; Weng, Eddie Feng-Ju ; Wu, Hsuan-Cheng ; Su, Tsung-Ping ; Wang, Shao-Ming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-41cf39d38dfb195b88eb6e5fd911f15059e5908a9e47d71a67520c178d1efa133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Active Transport, Cell Nucleus - drug effects</topic><topic>Alzheimer's disease</topic><topic>Amyotrophic lateral sclerosis</topic><topic>Animals</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>C9orf72 Protein - genetics</topic><topic>C9orf72 Protein - metabolism</topic><topic>Cell Biology</topic><topic>Cell death</topic><topic>Cell Line</topic><topic>Cell Nucleus - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Dementia disorders</topic><topic>Fluvoxamine</topic><topic>Fluvoxamine - pharmacology</topic><topic>Frontotemporal dementia</topic><topic>Humans</topic><topic>Mice</topic><topic>Neurobiology</topic><topic>Neurodegenerative diseases</topic><topic>Neurology</topic><topic>Neuroprotection</topic><topic>Neurosciences</topic><topic>Nuclear transport</topic><topic>Protein expression</topic><topic>Receptors, sigma - metabolism</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA transport</topic><topic>Sigma-1 Receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Chun-Yu</creatorcontrib><creatorcontrib>Wu, Hsiang-En</creatorcontrib><creatorcontrib>Weng, Eddie Feng-Ju</creatorcontrib><creatorcontrib>Wu, Hsuan-Cheng</creatorcontrib><creatorcontrib>Su, Tsung-Ping</creatorcontrib><creatorcontrib>Wang, Shao-Ming</creatorcontrib><collection>Springer_OA刊</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Chun-Yu</au><au>Wu, Hsiang-En</au><au>Weng, Eddie Feng-Ju</au><au>Wu, Hsuan-Cheng</au><au>Su, Tsung-Ping</au><au>Wang, Shao-Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB</atitle><jtitle>Molecular neurobiology</jtitle><stitle>Mol Neurobiol</stitle><addtitle>Mol Neurobiol</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>61</volume><issue>8</issue><spage>5282</spage><epage>5294</epage><pages>5282-5294</pages><issn>0893-7648</issn><issn>1559-1182</issn><eissn>1559-1182</eissn><abstract>Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer’s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G
4
C
2
)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G
4
C
2
)
31
-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In
C9orf72
-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G
4
C
2
)
31
-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with
C9orf72
-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G
4
C
2
)
31
-RNA-expressing NSC34 cells.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>38180612</pmid><doi>10.1007/s12035-023-03885-9</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-1479-9100</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Active Transport, Cell Nucleus - drug effects Alzheimer's disease Amyotrophic lateral sclerosis Animals Autophagy Autophagy - drug effects Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Biomedical and Life Sciences Biomedicine C9orf72 Protein - genetics C9orf72 Protein - metabolism Cell Biology Cell death Cell Line Cell Nucleus - drug effects Cell Nucleus - metabolism Dementia disorders Fluvoxamine Fluvoxamine - pharmacology Frontotemporal dementia Humans Mice Neurobiology Neurodegenerative diseases Neurology Neuroprotection Neurosciences Nuclear transport Protein expression Receptors, sigma - metabolism Ribonucleic acid RNA RNA transport Sigma-1 Receptor |
title | Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB |
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