Truncated tau disrupts autophagy and lysosomal biogenesis

Truncated tau disrupts autophagy and lysosomal biogenesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Truncated tau disrupts autophagy and lysosomal biogenesis Dina Dakkak, Saskia Pollack, Tong Guo, George Chennell, Patricia Gomez Suaga, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1522321/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 4 You are reading this latest preprint version Abstract The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, including Alzheimer’s disease and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, reduces beclin-1 and microtubule-associated protein 1A/1B-light chain 3, indicating that Tau35 disrupts autophagy in cells. We demonstrate that Tau35 reduces autophagic flux by blocking activation of 5' AMP-activated protein kinase and activating mammalian target of rapamycin complex 1 (mTORC1), as seen by increased phosphorylation of S6 ribosomal protein and a reduction in phosphorylated raptor. Tau35 also induces neutral lipid accumulation in cells, indicating a block of autophagic clearance and a deficit in lysosomal degradative capacity. In support of this view, reductions in lysosomal-associated membrane protein 2 and cathepsin D in cells expressing Tau35 are accompanied by its increased colocalisation with lysosomes. These deleterious effects of Tau35 on autophagy are not apparent with full-length tau, indicating that sequences in the amino-terminal half of tau may be involved in the regulation of mTORC1 and autophagic activity. Notably, upon induction of autophagy by Torin 1, both Tau35 and full-length tau inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. These findings implicate autophagic and lysosomal dysfunction as key pathological mechanisms through which abnormal tau could lead to the development and progression of tauopathy. Tau dementia Alzheimer’s disease autophagy lysosomes TFEB Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Cite Share Download PDF Status: Under Revision Version 1 posted Reviews received at journal 11 Apr, 2022 Reviewers invited by journal 07 Apr, 2022 Editor assigned by journal 05 Apr, 2022 First submitted to journal 04 Apr, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1522321","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":96976639,"identity":"be080fe7-df9c-450c-8f06-649138aab291","order_by":0,"name":"Dina Dakkak","email":"","orcid":"","institution":"King's College London Institute of Psychiatry Psychology and Neuroscience","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dina","middleName":"","lastName":"Dakkak","suffix":""},{"id":96976640,"identity":"030db5e4-3ece-4d9a-8761-bf5861a8831e","order_by":1,"name":"Saskia Pollack","email":"","orcid":"","institution":"King's College London Institute of Psychiatry Psychology and Neuroscience","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saskia","middleName":"","lastName":"Pollack","suffix":""},{"id":96976641,"identity":"222c7261-9fd9-4615-87e9-f90c7472246a","order_by":2,"name":"Tong Guo","email":"","orcid":"","institution":"King's College London Institute of Psychiatry Psychology and Neuroscience","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tong","middleName":"","lastName":"Guo","suffix":""},{"id":96976642,"identity":"17ab3cc0-c18f-40fa-8f8c-f44b6ef963e8","order_by":3,"name":"George Chennell","email":"","orcid":"","institution":"King's College London Institute of Psychiatry Psychology and Neuroscience","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"George","middleName":"","lastName":"Chennell","suffix":""},{"id":96976643,"identity":"3eafc2f1-399d-4c17-8346-eadfcb75a6bd","order_by":4,"name":"Patricia Gomez Suaga","email":"","orcid":"","institution":"King's College London Institute of Psychiatry Psychology and Neuroscience","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"Gomez","lastName":"Suaga","suffix":""},{"id":96976644,"identity":"6eecdc35-c1d2-4501-8d59-3ca98987fcec","order_by":5,"name":"Wendy Noble","email":"","orcid":"","institution":"King's College London Institute of Psychiatry Psychology and Neuroscience","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wendy","middleName":"","lastName":"Noble","suffix":""},{"id":96976645,"identity":"0da83b98-322b-40d0-828d-ad2998e0562f","order_by":6,"name":"Diane P Hanger","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDCCw2DyAITz4QCDDAOyAEEtjDMOMPAQ1nIAiWTmIUYL33HmZw8+MNyRN+dffOyzzRk7Hgb2ww+Yec7g1iJ5mM3ccAbDM8OdM54lz865kczDwJNmwMxzA7cWg8MMZtI8DIcZN9w4Y8yc8+EA0GE5QBd+wKeF/Zv0H4bD9htunP/MbAHSwv+GkBYeM2lguCVuON/DzMxwA6hFAmQLHodJHuYpk+wxOJy84QabMWPPmWQeNolnBgfn4PE+3/nj2yR+VBy23XD+8GOGH8fs5Pj5kx8+eHMMtxao84BYIgHCZmPAH5FIgJ9IdaNgFIyCUTDyAACAKVTZXABgwwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-3044-9816","institution":"King's College London","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Diane","middleName":"P","lastName":"Hanger","suffix":""}],"badges":[],"createdAt":"2022-04-04 14:44:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1522321/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1522321/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20213792,"identity":"da8bc9cf-7960-4ec1-891f-a4f6045ec3cf","added_by":"auto","created_at":"2022-04-11 20:35:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1807267,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 reduces the autophagy markers LC3 and beclin-1\u003c/p\u003e\u003cp\u003eWestern blots of cell lysates prepared from CHO-FL, CHO-Tau35 and CHO cells probed with antibodies recognising (a) total and phosphorylated (PHF1) tau, (b) beclin-1 (n=3), and (c) LC3-I/II (n=4), with β-actin as loading control. Molecular weights (kDa) are shown on the left. Graphs show quantitation of proteins relative to β-actin (mean ± SEM). One-way ANOVA with Tukey’s multiple comparisons test, *P\u0026lt;0.05, **P\u0026lt;0.01, ****P\u0026lt;0.0001. (d) Immunofluorescence of methanol-fixed CHO-FL, CHO-Tau35 and CHO cells labelled with antibody to LC3 (red) and Hoescht 33342 (blue). Scale bar=10 μm. Graph shows LC3 intensity per μm2 cell area (mean ± SEM, n=30 cells from 3 independent experiments for each cell line). Welch ANOVA with Dunnett’s T3 multiple comparisons test, *P\u0026lt;0.05, ****P\u0026lt;0.0001. (e) Paraformaldehyde-fixed CHO-FL, CHO-Tau35 and CHO cells transfected with 1 μg EGFP-LC3 plasmid (green). Scale bar=10 μm. Graph shows the number of EGFP-LC3 puncta per μm2 cell area (mean ± SEM, n=70-100 cells from 3 independent experiments for each cell line). Kruskal-Wallis with Dunn’s multiple comparisons test, **P\u0026lt;0.01, ****P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/06f6b14f7b5245927eb9ad63.png"},{"id":20213994,"identity":"bfc38857-9db7-41d6-8a19-75ba914e724e","added_by":"auto","created_at":"2022-04-11 20:40:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1629211,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 and FL tau affect the formation of autophagosomes and autolysosomes\u003c/p\u003e\u003cp\u003e(a) Paraformaldhyde-fixed CHO-FL, CHO-Tau35 and CHO cells transduced with mCherry-GFP-LC3 lentivirus for 72 h. Insets show zoomed in regions in the white dashed box. Scale bar=10 μm. Graphs show (b) the number of mCherry+GFP+ (autophagosomes) puncta and mCherry+GFP- (autolysosomes) puncta per μm2 cell area and (c) the sizes of autophagosomes and autolysosomes. Values shown are mean ± SEM, n=37-40 cells from a single transduction for each cell line. Kruskal-Wallis with Dunn’s multiple comparisons test, **P\u0026lt;0.01, ***P\u0026lt;0.001, ****P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/c5ec04c2f1f0da30b87cd275.png"},{"id":20213794,"identity":"7fc6c2bd-2d44-4c8d-af97-f9e8e55ef6b5","added_by":"auto","created_at":"2022-04-11 20:35:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":193226,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 impairs autophagy flux\u003c/p\u003e\u003cp\u003eWestern blots of CHO-FL, CHO-Tau35 and CHO cell lysates probed with antibodies to LC3-I/II and β-actin. Cells were treated with (a) bafilomycin A1 (300 nM, 2 h) or (b) rapamycin (1 μM, 6 h). Molecular weights (kDa) are shown on the left. Graphs show quantitation of LC3-II relative to β-actin under each condition. Values shown are mean ± SEM (n=3). Two-way ANOVA with Sidak’s multiple comparisons test, *P\u0026lt;0.05, ***P\u0026lt;0.001, ****P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/d036317ed31fd42150b9e230.png"},{"id":20213199,"identity":"76bb4c80-3ff9-4fef-8d2e-9ff534a862cf","added_by":"auto","created_at":"2022-04-11 20:30:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":385392,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 inhibits the clearance of neutral lipid droplets\u003c/p\u003e\u003cp\u003eLabelling of paraformaldehyde-fixed CHO-FL, CHO-Tau35 and CHO cells with BODIPY 493/503 (green) and Hoescht 33342 (blue). Scale bar=10 μm. Graphs show the number of BODIPY puncta per μm2 cell area. Values shown are mean ± SEM, n=30 cells from 3 independent experiments for each cell line. Kruskal-Wallis with Dunn’s multiple comparisons test, ***P\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/6c26080d03eebdb1d06ce083.png"},{"id":20213205,"identity":"326d6c50-f882-40a1-9264-9a7626f2e341","added_by":"auto","created_at":"2022-04-11 20:30:30","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2583479,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 leads to lysosomal deficits\u003c/p\u003e\u003cp\u003e(a) Labelling of acidic structures using LysoTracker Red in CHO-FL, CHO-Tau35 and CHO cells. Scale bar=10 μm. Graph shows the number of LysoTracker positive puncta per μm2 cell area. Values are shown as mean ± SEM, n=30-40 cells from 3 independent experiments for each cell line. Welch ANOVA with Dunnett’s T3 multiple comparisons test, ****P\u0026lt;0.0001, *P\u0026lt;0.05. (b) Labelling of paraformaldehyde-fixed CHO-FL, CHO-Tau35 and CHO cells with antibodies to LAMP2 (green), cathepsin D (red), and Hoescht 33342 (blue). Scale bar=10 μm. Graphs show the number of LAMP2 and cathepsin D puncta per cell, standardised to cell area. Values shown are mean ± SEM, n=30 cells from 3 independent experiments for each cell line. Welch ANOVA with Dunnett’s T3 multiple comparisons test, ****P\u0026lt;0.0001. (c) Immunofluorescence of paraformaldehyde-fixed CHO-FL and CHO-Tau35 cells labelled with antibodies to LAMP2 (green), tau (red), and Hoescht 33342 (blue). Scale bar=10 μm. Graph shows the Pearson correlation coefficient for LAMP2 and tau in CHO-FL and CHO-Tau35 cells. Values shown are mean ± SEM, n=30 cells from 3 independent experiments for each cell line. Unpaired t-test with Welch’s correction, ****P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/59f6387e7cbdc7aef1a2b1f2.png"},{"id":20213203,"identity":"a87dcbe1-b1b0-4676-9cac-93b71ba7ec54","added_by":"auto","created_at":"2022-04-11 20:30:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":638113,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 leads to defects in the expression of TFEB-regulated genes\u003c/p\u003e\u003cp\u003e(a) Graphs of RT-qPCR analyses showing the relative quantification (RQ) of mRNA expression, using CHO cells as control. Data show mean ± SEM from 3 independent experiments for each cell line. RT-qPCR was performed on Tfeb, Lamp1, Lamp2 and Ctsd and normalised to Gapdh and Actb. One-way ANOVA with Tukey’s multiple comparisons test, *P\u0026lt;0.05, **P\u0026lt;0.01. (b) Western blots of CHO-FL, CHO-Tau35 and CHO cell lysates probed with antibodies to TFEB and β-actin. The lanes were re-ordered from the same blot. Molecular weights (kDa) are shown on the left. Arrows indicate the TFEB doublet. The graph show quantitation of total TFEB relative to β-actin (n=3). (c) Immunofluorescence of paraformaldehyde-fixed CHO-FL, CHO-Tau35 and CHO cells labelled with antibody to TFEB (red) and Hoescht 33342 (blue). Scale bar=10 μm. Graph shows the percentage of cells with nuclear TFEB (n=240-300 cells from each condition, 3 independent experiments). (d) Paraformaldehyde-fixed CHO-FL, CHO-Tau35 and CHO cells expressing EGFP-TFEB (green) labelled with Hoechst 33342 (blue). Scale bar=10 μm. Graph shows the percentage of cells exhibiting nuclear TFEB (n=330-540 cells/5-10 fields of view of each cell type, 3 independent experiments). One-way ANOVA with Tukey’s multiple comparisons test, **P\u0026lt;0.01. (e) CHO-FL, CHO-Tau35 and CHO cells treated with 1 M Torin 1 (T1) for 2 h or vehicle (V) were separated into nuclear and cytoplasmic fractions and probed on western blots with antibodies to TFEB, GAPDH and histone H3. C: cytoplasmic fraction, N: nuclear fraction. Graphs show quantification of the normalised nuclear/cytoplasmic TFEB ratio (n=3). Two-way ANOVA with Sidak’s multiple comparisons test, *P\u0026lt;0.05, **P\u0026lt;0.01, ****P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/32662e3ad6e107bbaad24806.png"},{"id":20213202,"identity":"8de580f9-43fe-4896-ae2a-3eccb6c4d370","added_by":"auto","created_at":"2022-04-11 20:30:30","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":154617,"visible":true,"origin":"","legend":"\u003cp\u003eTau35 expression activates mTORC1 and reduces AMPK activity\u003c/p\u003e\u003cp\u003eWestern blots of CHO-FL, CHO-Tau35 and CHO cell lysates probed with antibodies to (a) phosphorylated and total S6 (n=6), (b) phosphorylated and total raptor (n=6), and (c) phosphorylated and total AMPK (n=3). Molecular weights (kDa) are shown on the left. Graphs show quantitation of the phosphorylated/total proteins (mean ± SEM). One-way ANOVA with Tukey’s multiple comparisons test, *P\u0026lt;0.05, **P\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1/14d9b1c70f20ad1f836997d0.png"},{"id":20213996,"identity":"90d7ccdd-bcde-490c-aa28-2b59a164d33a","added_by":"auto","created_at":"2022-04-11 20:40:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":393396,"visible":true,"origin":"","legend":"","description":"","filename":"20220404Manuscriptfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1522321/v1_covered.pdf"}],"financialInterests":"","formattedTitle":"Truncated tau disrupts autophagy and lysosomal biogenesis","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-1522321/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Tau, dementia, Alzheimer’s disease, autophagy, lysosomes, TFEB","lastPublishedDoi":"10.21203/rs.3.rs-1522321/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1522321/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, including Alzheimer’s disease and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, reduces beclin-1 and microtubule-associated protein 1A/1B-light chain 3, indicating that Tau35 disrupts autophagy in cells. We demonstrate that Tau35 reduces autophagic flux by blocking activation of 5' AMP-activated protein kinase and activating mammalian target of rapamycin complex 1 (mTORC1), as seen by increased phosphorylation of S6 ribosomal protein and a reduction in phosphorylated raptor. Tau35 also induces neutral lipid accumulation in cells, indicating a block of autophagic clearance and a deficit in lysosomal degradative capacity. In support of this view, reductions in lysosomal-associated membrane protein 2 and cathepsin D in cells expressing Tau35 are accompanied by its increased colocalisation with lysosomes. These deleterious effects of Tau35 on autophagy are not apparent with full-length tau, indicating that sequences in the amino-terminal half of tau may be involved in the regulation of mTORC1 and autophagic activity. Notably, upon induction of autophagy by Torin 1, both Tau35 and full-length tau inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. These findings implicate autophagic and lysosomal dysfunction as key pathological mechanisms through which abnormal tau could lead to the development and progression of tauopathy.\u003c/p\u003e","manuscriptTitle":"Truncated tau disrupts autophagy and lysosomal biogenesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-11 20:30:28","doi":"10.21203/rs.3.rs-1522321/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2022-04-11T07:49:54+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-04-07T19:06:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-04-05T08:42:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular and Molecular Life Sciences","date":"2022-04-04T10:25:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"429b5ec2-e230-4223-98f6-a529963d4732","owner":[],"postedDate":"April 11th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2022-07-28T02:36:33+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-11 20:30:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1522321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1522321","identity":"rs-1522321","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}