1. UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS.
- Author
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Black HH, Hanson JL, Roberts JE, Leslie SN, Campodonico W, Ebmeier CC, Holling GA, Tay JW, Matthews AM, Ung E, Lau CI, and Whiteley AM
- Subjects
- Humans, Retroelements, Adaptor Proteins, Signal Transducing metabolism, Motor Neurons metabolism, Mutation, Autophagy-Related Proteins metabolism, Ubiquitins metabolism, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, RNA-Binding Proteins metabolism, Apoptosis Regulatory Proteins metabolism, Amyotrophic Lateral Sclerosis genetics, Neurodegenerative Diseases genetics
- Abstract
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., Competing Interests: HB, JH, JR, SL, WC, CE, GH, JT, AM, EU, CL No competing interests declared, AW The University of Colorado, Boulder, has a patent pending for the use of PEG10 inhibitors on which the author is an inventor, (© 2023, Black, Hanson et al.)
- Published
- 2023
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