| First Author | Li D | Year | 2023 |
| Journal | Nat Aging | Volume | 3 |
| Issue | 8 | Pages | 1001-1019 |
| PubMed ID | 37474791 | Mgi Jnum | J:340113 |
| Mgi Id | MGI:7525752 | Doi | 10.1038/s43587-023-00464-4 |
| Citation | Li D, et al. (2023) LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits. Nat Aging 3(8):1001-1019 |
| abstractText | 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. |
