Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Autor:	Seddighi S; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Nuffield Department of Population Health, University of Oxford, Oxford, UK., Qi YA; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Brown AL; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Wilkins OG; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.; Francis Crick Institute, London, UK., Bereda C; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Belair C; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Zhang YJ; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Prudencio M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Keuss MJ; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Khandeshi A; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Pickles S; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Kargbo-Hill SE; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Hawrot J; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Ramos DM; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Yuan H; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Roberts J; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Sacramento EK; Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany., Shah SI; Data Tecnica International, Washington, DC, USA., Nalls MA; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Data Tecnica International, Washington, DC, USA., Colón-Mercado JM; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Reyes JF; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Ryan VH; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Nelson MP; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Cook CN; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Li Z; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Data Tecnica International, Washington, DC, USA., Screven L; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Kwan JY; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Mehta PR; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Zanovello M; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Hallegger M; Francis Crick Institute, London, UK.; UK Dementia Research Institute at King's College London, London, UK., Shantaraman A; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Ping L; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Koike Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Oskarsson B; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Staff NP; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Duong DM; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA., Ahmed A; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Secrier M; Department of Genetics, Evolution and Environment, UCL Genetics Institute, UCL, London, UK., Ule J; Francis Crick Institute, London, UK.; UK Dementia Research Institute at King's College London, London, UK., Jacobson S; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Reich DS; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Rohrer JD; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Malaspina A; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Glass JD; Department of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA., Ori A; Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany., Seyfried NT; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA., Maragkakis M; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA., Fratta P; UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.; Francis Crick Institute, London, UK., Ward ME; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2024 Feb 14; Vol. 16 (734), pp. eadg7162. Date of Electronic Publication: 2024 Feb 14.
DOI:	10.1126/scitranslmed.adg7162
Abstrakt:	Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.
Databáze:	MEDLINE
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