LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits

Nat Aging. 2023 Aug;3(8):1001-1019. doi: 10.1038/s43587-023-00464-4. Epub 2023 Jul 20.


Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / genetics
  • Ligases / metabolism
  • Mice
  • Motor Neurons* / metabolism
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • RNA Helicases / metabolism
  • RNA Recognition Motif Proteins / metabolism
  • Ubiquitin* / metabolism
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism


  • DNA Helicases
  • DNA-Binding Proteins
  • Ligases
  • Poly-ADP-Ribose Binding Proteins
  • RNA Helicases
  • RNA Recognition Motif Proteins
  • Ubiquitin
  • Lonrf2 protein, mouse
  • Ubiquitin-Protein Ligases