Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology
| Autor: | Paul Lopatta, Ravi Jagasia, Rasmussen Søren Vestergaard, Tom Dunkley, Marco Berrera, Nikhil J. Pandya, Edwin Mientjes, Tania Distler, Ben Distel, Balazs Banfai, F. Isabella Zampeta, Ype Elgersma, Philip Grossen, Christoph Patsch, Martin Ebeling, Thomas Kremer, Sonja Meier, Yasmina Martí, A. Mattijs Punt, Congwei Wang, Veronica Costa, Manuel Tzouros, Marius C. Hoener |
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| Přispěvatelé: | Clinical Genetics, Neurosciences, Medical Biochemistry, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Proteasome Endopeptidase Complex congenital hereditary and neonatal diseases and abnormalities Retroelements RNA-binding protein Ubiquitin-Protein Ligases Induced Pluripotent Stem Cells Gene Products gag Biology General Biochemistry Genetics and Molecular Biology hiPSC neurons Extracellular Vesicles Stress granule Protein Domains SDG 3 - Good Health and Well-being Cell Movement Angelman syndrome UBE3A medicine Animals Humans PEG10 Neurons Ubiquitin-Protein Ligase E3A RNA retroviral GAG nutritional and metabolic diseases RNA-Binding Proteins Group-specific antigen medicine.disease Preview Stress Granules Cell biology nervous system diseases DNA-Binding Proteins Mice Inbred C57BL Retroviridae Proteasome Child Preschool Female Angelman Syndrome Apoptosis Regulatory Proteins Transcriptome |
| Zdroj: | Cell Reports Medicine Cell Reports Medicine, 2(8):100360. Cell Press |
| ISSN: | 2666-3791 |
| Popis: | Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology. |
| Databáze: | OpenAIRE |
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