14 Jun ALS: Gene That Acts Like Ancient Virus May Play Role in Neurodegeneration
MedicalResearch.com Interview with:
Alexandra M Whiteley PhD
Department of Biochemistry
University of Colorado Boulder
MedicalResearch.com: What is the background for this study?
Response: My laboratory was interested in understanding how UBQLN2 maintains cellular health. Ubiquilins facilitate protein degradation, but the precise proteins that they help to break down were not well understood. UBQLN2 is of particular interest because mutations in the UBQLN2 gene lead to a familial form of ALS.
This project, which was published in eLife this year, stems from work that was published when I was a postdoctoral researcher at Harvard Medical School, where we found a link between UBQLN2 and the virus-like protein PEG10. Now at the University of Colorado, Boulder, my laboratory has focused on trying to understand this connection between the two proteins, and how PEG10 could contribute to ALS.
MedicalResearch.com: What are the main findings? Where did these viral particles come from?
Response: The main findings are two-fold:
-First, we found that PEG10, while a human gene, behaves a bit like a virus in cells. Like its viral ancestors, PEG10 cleaves itself into small pieces, one of which binds to RNA and moves to the nucleus. That little piece, by itself, is capable of changing gene expression in the cell – specifically, genes involved in axon remodeling and neuron communication.
Second, we found that the PEG10 protein is upregulated in the spinal cords of ALS patients as compared to controls.
Together, they suggest a molecular pathway whereby the mutation of UBQLN2 leads to neurodegeneration.
I should clarify that our study does not directly examine the virus-like particles made by PEG10 (note that PEG10 is not a virus). We did confirm other studies that show that PEG10 is capable of making virus-like particles, but we have not examined their presence in neurodegenerative disease, nor do we know what they do.
MedicalResearch.com: What should readers take away from your report?
Response: To me, one of the most exciting parts of the study is the realization that there are genes in our bodies that act more like viruses than we realize. PEG10 is derived from an ancient retrotransposon called Ty3 and ‘inserted’ into the mammalian genome right after monotremes (platypus, etc.) branched away from marsupials (koala, etc.) and placental mammals (us). PEG10 is essential for development of a placenta, but appears to be harmful for neuronal health. How amazing that our bodies are having to balance the helpful and harmful roles of PEG10, and that UBQLN2 seems to be a major player in that balance!
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: There is a lot of work to be done as a result of our study. We want to examine larger groups of ALS patients to examine how universal the accumulation of PEG10 is. We also want to understand the mechanism by which PEG10 influences gene expression in the cell; how does that little protein fragment cause changes to axon remodeling genes? And finally, we’re taking a big step to determine just how important PEG10 is to the neurodegenerative process with UBQLN2-mediated animal models of fALS. If we get rid of PEG10 expression, are the animals protected from disease?
Disclosures: Some of the authors on our study are inventors on a submitted patent for the use of PEG10 as a biomarker of disease.
Black HH, Hanson JL, Roberts JE, Leslie SN, Campodonico W, Ebmeier CC, Holling GA, Tay JW, Matthews AM, Ung E, Lau CI, Whiteley AM. UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS. Elife. 2023 Mar 23;12:e79452. doi: 10.7554/eLife.79452. PMID: 36951542; PMCID: PMC10076021.
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