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Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants
Laura Strohm1, Zehan Hu2, Yongwon Suk3
1Munich Cluster for Systems Neurology, Medical Faculty, Ludwig-Maximilians-University München, Munich, Germany.
Life Science Alliance
|July 1, 2022
Summary
Mutations in Ubiquilin-2 (UBQLN2) linked to ALS/FTD disrupt protein degradation. This study reveals a UBQLN2-FUS-MAP1B pathway affecting RNA metabolism and cytoskeleton dynamics in neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein crucial for protein degradation via proteasomal and autophagic pathways.
- Mutations in UBQLN2 are genetically associated with neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD).
- The precise molecular mechanisms by which UBQLN2 mutations lead to ALS/FTD remain largely unknown.
Purpose of the Study:
- To elucidate the molecular consequences of UBQLN2 mutations in ALS/FTD.
- To investigate the link between UBQLN2 dysfunction, microtubule-associated protein 1B (MAP1B), and fused in sarcoma (FUS) protein.
- To identify key pathways disrupted by UBQLN2 mutations relevant to ALS/FTD pathogenesis.
Main Methods:
- Proteomic and transcriptomic analyses were performed on patient-derived lymphoblasts and engineered HeLa cells with UBQLN2 mutations.
- UBQLN2 knockout cells and primary rodent neurons were utilized to confirm findings.
- Western blotting and phosphorylation site analysis were employed to assess protein levels and modifications.
Main Results:
- A significant upregulation of microtubule-associated protein 1B (MAP1B) was consistently observed in cells with UBQLN2 mutations or depletion, indicating a loss-of-function mechanism.
- Increased levels of total and acetylated tubulin suggest alterations in microtubule dynamics.
- UBQLN2 mutations led to decreased phosphorylation of MAP1B and the FUS protein at S439, impacting FUS-RNA binding and MAP1B stability.
Conclusions:
- The study identifies a deregulated UBQLN2-FUS-MAP1B axis as a potential mechanism linking protein homeostasis, RNA metabolism, and cytoskeleton dynamics in ALS/FTD.
- UBQLN2 loss-of-function contributes to elevated MAP1B levels and altered microtubule function.
- These findings provide novel insights into the molecular pathogenesis of ALS/FTD and suggest potential therapeutic targets.
