@article {Strohme202101327, author = {Laura Strohm and Zehan Hu and Yongwon Suk and Alina R{\"u}hmkorf and Erin Sternburg and Vanessa Gattringer and Henrick Riemenschneider and Riccardo Berutti and Elisabeth Graf and Jochen H Weishaupt and Monika S Brill and Angelika B Harbauer and Dorothee Dormann and J{\"o}rn Dengjel and Dieter Edbauer and Christian Behrends}, title = {Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD{\textendash}associated UBQLN2 mutants}, volume = {5}, number = {11}, elocation-id = {e202101327}, year = {2022}, doi = {10.26508/lsa.202101327}, publisher = {Life Science Alliance}, 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{\textendash}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{\textquoteright}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{\textendash}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.}, URL = {https://www.life-science-alliance.org/content/5/11/e202101327}, eprint = {https://www.life-science-alliance.org/content/5/11/e202101327.full.pdf}, journal = {Life Science Alliance} }