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

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. Many age-related disorders, such as neurodegenerative diseases, are associated with protein misfolding. Here, the authors identify LONRF2 as a protein quality control ubiquitin ligase that is expressed in neurons and ubiquitylates misfolded TDP-43 and hnRNP M1 and show that loss of Lonrf2 in mice results in late-onset motor neuron degeneration, whereas its ectopic expression partially rescued the phenotypes observed in motor neurons derived from patients with amyotrophic lateral sclerosis.