UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS

Amyotrophic Lateral Sclerosis (ALS) is a fatal, neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate a function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon paternally expressed gene 10 (PEG10) in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated nucleocapsid fragment, which uniquely localizes to the nucleus and changes expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.