RT Journal Article
SR Electronic
T1 Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101327
DO 10.26508/lsa.202101327
VO 5
IS 11
A1 Laura Strohm
A1 Zehan Hu
A1 Yongwon Suk
A1 Alina Rühmkorf
A1 Erin Sternburg
A1 Vanessa Gattringer
A1 Henrick Riemenschneider
A1 Riccardo Berutti
A1 Elisabeth Graf
A1 Jochen H Weishaupt
A1 Monika S Brill
A1 Angelika B Harbauer
A1 Dorothee Dormann
A1 Jörn Dengjel
A1 Dieter Edbauer
A1 Christian Behrends
YR 2022
UL https://www.life-science-alliance.org/content/5/11/e202101327.abstract
AB 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.