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

Elife. 2023 Mar 23:12:e79452. doi: 10.7554/eLife.79452.


Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are 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 that UBQLN2 regulates 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 the 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 the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

Keywords: ALS; PEG10; UBQLN2; cell biology; domesticated retrotransposon; human; neuroscience; proteomics; ubiquilin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Amyotrophic Lateral Sclerosis* / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy-Related Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Humans
  • Motor Neurons / metabolism
  • Mutation
  • Neurodegenerative Diseases* / genetics
  • RNA-Binding Proteins / metabolism
  • Retroelements
  • Ubiquitins / metabolism


  • Retroelements
  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Ubiquitins
  • Cell Cycle Proteins
  • PEG10 protein, human
  • DNA-Binding Proteins
  • RNA-Binding Proteins
  • Apoptosis Regulatory Proteins
  • UBQLN2 protein, human

Associated data

  • GEO/GSE227789