Transcript errors generate amyloid-like proteins in human cells

Claire S. Chung, Yi Kou, Sarah J. Shemtov, Bert M. Verheijen, Ilse Flores, Kayla Love, Ashley Dosso, Max A. Thorwald, Yuchen Liu, Daniel Hicks, Yingwo Sun, Renaldo G. Toney, Lucy Carrillo, Megan M. Nguyen, Huang Biao, Yuxin Jin, Ashley Michelle Jauregui, Juan Diaz Quiroz, Elizabeth Head, Darcie L. Moore, Stephen Simpson, Kelley W. Thomas, Marcelo P. Coba, Zhongwei Li, Bérénice A. Benayoun, Joshua J. C. Rosenthal, Scott R. Kennedy, Giorgia Quadrato, Jean-Francois Gout, Lin Chen and Marc Vermulst ()
Additional contact information
Claire S. Chung: Leonard Davis School of Gerontology
Yi Kou: Molecular and Cellular Biology Department
Sarah J. Shemtov: Leonard Davis School of Gerontology
Bert M. Verheijen: Leonard Davis School of Gerontology
Ilse Flores: Keck School of Medicine
Kayla Love: Molecular and Cellular Biology Department
Ashley Dosso: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
Max A. Thorwald: Leonard Davis School of Gerontology
Yuchen Liu: Molecular and Cellular Biology Department
Daniel Hicks: Leonard Davis School of Gerontology
Yingwo Sun: Leonard Davis School of Gerontology
Renaldo G. Toney: Leonard Davis School of Gerontology
Lucy Carrillo: Leonard Davis School of Gerontology
Megan M. Nguyen: Department of Pathology and Laboratory Medicine
Huang Biao: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
Yuxin Jin: Keck School of Medicine
Ashley Michelle Jauregui: Keck School of Medicine
Juan Diaz Quiroz: Bell Center
Elizabeth Head: Department of Pathology and Laboratory Medicine
Darcie L. Moore: Department of Neuroscience
Stephen Simpson: & Biomedical Sciences
Kelley W. Thomas: & Biomedical Sciences
Marcelo P. Coba: Keck School of Medicine
Zhongwei Li: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
Bérénice A. Benayoun: Leonard Davis School of Gerontology
Joshua J. C. Rosenthal: Bell Center
Scott R. Kennedy: Department of Pathology and Laboratory Medicine
Giorgia Quadrato: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
Jean-Francois Gout: Department of Biology
Lin Chen: Molecular and Cellular Biology Department
Marc Vermulst: Leonard Davis School of Gerontology

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

Date: 2024
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DOI: 10.1038/s41467-024-52886-2

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