Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Laura Strohm
- Zehan Hu
- Yongwon Suk
- Alina Ruehmkorf
- Erin Sternburg
- Vanessa Gattringer
- Henrick Riemenschneider
- Riccardo Berutti
- Elisabeth Graf
- Jochen H Weishaupt
- Monika S Brill
- Angelika B Harbauer
- Dorothee Dormann
- Jorn Dengjel
- Dieter Edbauer
- Christian Behrends
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000823596600001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.26508/lsa.202101327
- eISSN
- 2575-1077
- Externe Identifier
- Clarivate Analytics Document Solution ID: 2V1EY
- PubMed Identifier: 35777956
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- LIFE SCIENCE ALLIANCE
- Artikelnummer
- ARTN e202101327
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Titel
- Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants
- Sub types
- Article
- Ausgabe der Zeitschrift
- 5
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9–engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B’s role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD–linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD.</jats:p>
- Autoren
- Laura Strohm
- Zehan Hu
- Yongwon Suk
- Alina Rühmkorf
- Erin Sternburg
- Vanessa Gattringer
- Henrick Riemenschneider
- Riccardo Berutti
- Elisabeth Graf
- Jochen H Weishaupt
- Monika S Brill
- Angelika B Harbauer
- Dorothee Dormann
- Jörn Dengjel
- Dieter Edbauer
- Christian Behrends
- DOI
- 10.26508/lsa.202101327
- eISSN
- 2575-1077
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Life Science Alliance
- Sprache
- en
- Online publication date
- 2022
- Paginierung
- e202101327 - e202101327
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Herausgeber
- Life Science Alliance, LLC
- Herausgeber URL
- http://dx.doi.org/10.26508/lsa.202101327
- Datum der Datenerfassung
- 2024
- Titel
- Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
- Ausgabe der Zeitschrift
- 5
Data source: Crossref
- Abstract
- Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9-engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B's role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD-linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD.
- Addresses
- Munich Cluster for Systems Neurology, Medical Faculty, Ludwig-Maximilians-University München, Munich, Germany.
- Autoren
- Laura Strohm
- Zehan Hu
- Yongwon Suk
- Alina Rühmkorf
- Erin Sternburg
- Vanessa Gattringer
- Henrick Riemenschneider
- Riccardo Berutti
- Elisabeth Graf
- Jochen H Weishaupt
- Monika S Brill
- Angelika B Harbauer
- Dorothee Dormann
- Jörn Dengjel
- Dieter Edbauer
- Christian Behrends
- DOI
- 10.26508/lsa.202101327
- eISSN
- 2575-1077
- Externe Identifier
- PubMed Identifier: 35777956
- PubMed Central ID: PMC9258132
- Funding acknowledgements
- Collaborative Research Center: 259130777
- Deutsche Forschungsgemeinschaft: 390857198
- Open access
- true
- ISSN
- 2575-1077
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Life science alliance
- Schlüsselwörter
- Hela Cells
- Humans
- Amyotrophic Lateral Sclerosis
- Adaptor Proteins, Signal Transducing
- RNA-Binding Protein FUS
- Microtubule-Associated Proteins
- Transcription Factors
- RNA
- Proteomics
- Frontotemporal Dementia
- Autophagy-Related Proteins
- Sprache
- eng
- Medium
- Electronic-Print
- Online publication date
- 2022
- Open access status
- Open Access
- Paginierung
- e202101327
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2022
- Titel
- Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 5
Files
https://www.life-science-alliance.org/content/lsa/5/11/e202101327.full.pdf https://europepmc.org/articles/PMC9258132?pdf=render
Data source: Europe PubMed Central
- Abstract
- Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9-engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B's role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD-linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD.
- Date of acceptance
- 2022
- Autoren
- Laura Strohm
- Zehan Hu
- Yongwon Suk
- Alina Rühmkorf
- Erin Sternburg
- Vanessa Gattringer
- Henrick Riemenschneider
- Riccardo Berutti
- Elisabeth Graf
- Jochen H Weishaupt
- Monika S Brill
- Angelika B Harbauer
- Dorothee Dormann
- Jörn Dengjel
- Dieter Edbauer
- Christian Behrends
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/35777956
- DOI
- 10.26508/lsa.202101327
- eISSN
- 2575-1077
- Externe Identifier
- PubMed Central ID: PMC9258132
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Life Sci Alliance
- Schlüsselwörter
- Adaptor Proteins, Signal Transducing
- Amyotrophic Lateral Sclerosis
- Autophagy-Related Proteins
- Frontotemporal Dementia
- HeLa Cells
- Humans
- Microtubule-Associated Proteins
- Proteomics
- RNA
- RNA-Binding Protein FUS
- Transcription Factors
- Sprache
- eng
- Country
- United States
- PII
- 5/11/e202101327
- Datum der Veröffentlichung
- 2022
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 5
Data source: PubMed
- Author's licence
- CC-BY
- Autoren
- Laura Strohm
- Zehan Hu
- Yongwon Suk
- Alina Rühmkorf
- Erin Sternburg
- Vanessa Gattringer
- Henrick Riemenschneider
- Riccardo Berutti
- Elisabeth Graf
- Jochen H Weishaupt
- Monika S Brill
- Angelika B Harbauer
- Dorothee Dormann
- Jörn Dengjel
- Dieter Edbauer
- Christian Behrends
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- JGU-Publikationen
- Resource version
- Published version
- DOI
- 10.26508/lsa.202101327
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 2575-1077
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- Life science alliance
- Schlüsselwörter
- 570 Biowissenschaften
- 570 Life sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- e202101327
- Datum der Veröffentlichung
- 2022
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/10273
- Herausgeber
- EMBO Press
- Datum der Datenerfassung
- 2024
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2024
- Zugang
- Public
- Titel
- Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants
- Ausgabe der Zeitschrift
- 5
Files
multiomics_profiling_identifi-20240331182415249.pdf
Data source: OPENSCIENCE.UB
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