Transcript errors generate amyloid-like proteins in human cells

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 organo...

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Published in:Nature communications 2024-10, Vol.15 (1), p.8676-17, Article 8676
Main Authors: Chung, Claire S., Kou, Yi, Shemtov, Sarah J., Verheijen, Bert M., Flores, Ilse, Love, Kayla, Del Dosso, Ashley, Thorwald, Max A., Liu, Yuchen, Hicks, Daniel, Sun, Yingwo, Toney, Renaldo G., Carrillo, Lucy, Nguyen, Megan M., Biao, Huang, Jin, Yuxin, Jauregui, Ashley Michelle, Quiroz, Juan Diaz, Head, Elizabeth, Moore, Darcie L., Simpson, Stephen, Thomas, Kelley W., Coba, Marcelo P., Li, Zhongwei, Benayoun, Bérénice A., Rosenthal, Joshua J. C., Kennedy, Scott R., Quadrato, Giorgia, Gout, Jean-Francois, Chen, Lin, Vermulst, Marc
Format: Article
Language:English
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Age related diseases
Aging
Alzheimer's disease
Amyotrophic lateral sclerosis
Brain damage
Cell differentiation
Disease
DNA damage
Errors
Genomes
Humanities and Social Sciences
Hypotheses
Molecular modelling
mRNA
multidisciplinary
Mutants
Mutation
Neurogenesis
Organoids
Pathology
Proteins
Science
Science (multidisciplinary)
Stem cells
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Summary: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. Amyloid-like proteins are central to age-related diseases, such as Alzheimer’s and Parkinson’s. Here, the authors show that transcription errors can produce mutant proteins with enhanced amyloid- and prion-like properties in human cells.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-52886-2