Mutant UBQLN2 promotes toxicity by modulating intrinsic self-assembly

Lisa M. Sharkey, Nathaniel Safren, Amit S. Pithadia, Julia E. Gerson, Mark Dulchavsky, Svetlana Fischer, Ronak Patel, Gabrielle Lantis, Naila Ashraf, John H. Kim, Alia Meliki, Eiko N. Minakawa, Sami J. Barmada*, Magdalena I. Ivanova, Henry L. Paulson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


UBQLN2 is one of a family of proteins implicated in ubiquitindependent protein quality control and integrally tied to human neurodegenerative disease. Whereas wild-type UBQLN2 accumulates in intraneuronal deposits in several common age-related neurodegenerative diseases, mutations in the gene encoding this protein result in X-linked amyotrophic lateral sclerosis/frontotemporal dementia associated with TDP43 accumulation. Using in vitro protein analysis, longitudinal fluorescence imaging and cellular, neuronal, and transgenic mouse models, we establish that UBQLN2 is intrinsically prone to self-assemble into higher-order complexes, including liquid-like droplets and amyloid aggregates. UBQLN2 selfassembly and solubility are reciprocally modulated by the protein's ubiquitin-like and ubiquitin-associated domains. Moreover, a pathogenic UBQLN2 missense mutation impairs droplet dynamics and favors amyloid-like aggregation associated with neurotoxicity. These data emphasize the critical link between UBQLN2's role in ubiquitin-dependent pathways and its propensity to self-assemble and aggregate in neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)E10495-E10504
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Oct 30 2018
Externally publishedYes


  • ALS
  • FTD
  • Liquid-liquid phase separation
  • Membraneless organelle
  • UBQLN2

ASJC Scopus subject areas

  • General


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