Buchumschlag

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

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 elus...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Hauptverfasser: Strohm, Laura (VerfasserIn) , Hu, Zehan (VerfasserIn) , Suk, Yongwon (VerfasserIn) , Rühmkorf, Alina (VerfasserIn) , Sternburg, Erin (VerfasserIn) , Gattringer, Vanessa (VerfasserIn) , Riemenschneider, Henrick (VerfasserIn) , Berutti, Riccardo (VerfasserIn) , Graf, Elisabeth (VerfasserIn) , Weishaupt, Jochen H. (VerfasserIn) , Leischner-Brill, Monika (VerfasserIn) , Harbauer, Angelika Bettina (VerfasserIn) , Dormann, Dorothee (VerfasserIn) , Dengjel, Jörn (VerfasserIn) , Edbauer, Dieter (VerfasserIn) , Behrends, Christian (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 1 July 2022
In: Life science alliance
Year: 2022, Jahrgang: 5, Heft: 11, Pages: 1-21
ISSN:2575-1077
DOI:10.26508/lsa.202101327
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.26508/lsa.202101327
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 08.08.2022
Beschreibung:Online Resource
ISSN:2575-1077
DOI:10.26508/lsa.202101327

Ähnliche Einträge