LONRF2 is a protein quality control ubiquitin ligase predominantly expressed in post-mitotic neurons that functions to recognize and ubiquitylate misfolded proteins 1. The protein specifically binds and targets abnormally structured TDP-43, hnRNP M1, and artificially misfolded substrates for degradation 1. LONRF2 is selectively induced in senescent post-mitotic cells, reflecting a specialized protein quality control system adapted to neurons, which cannot dilute protein aggregates through cell division 1. Loss of LONRF2 function results in age-dependent pathology: Lonrf2-deficient mice develop progressive motor neuron degeneration and cerebellar ataxia accompanied by TDP-43 accumulation 1. Motor neurons derived from LONRF2-knockout induced pluripotent stem cells show reduced survival, neurite shortening, and pathological accumulation of phosphorylated TDP-43 1. Critically, LONRF2 overexpression rescues neurite defects in motor neurons from amyotrophic lateral sclerosis patients, suggesting therapeutic potential 1. These findings establish LONRF2 as a critical neuroprotective protein quality control factor whose deficiency contributes to neurodegeneration.