Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
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

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
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

Datenquelle: 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

Datenquelle: 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

Datenquelle: 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

Datenquelle: OPENSCIENCE.UB

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