C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity
| Autor: | Pranetha Baskaran, Leonard Petrucelli, Frank Hirth, Bradley N. Smith, Claire Troakes, Alan Stepto, Youn-Bok Lee, Agnes L. Nishimura, Christopher Shaw, Jorge Gomez-Deza, Boris Rogelj, Yoshitsugu Adachi, Sarah Guthrie, Han-Jou Chen, Jean-Marc Gallo |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
medicine.medical_specialty
Intranuclear Inclusion Bodies Apoptosis Chick Embryo Computational biology Biology Protein Aggregates 03 medical and health sciences QH301 0302 clinical medicine C9orf72 Molecular genetics Genetics medicine Animals Humans Amyotrophic lateral sclerosis Molecular Biology Cells Cultured Genetics (clinical) 030304 developmental biology Neurons 0303 health sciences DNA Repeat Expansion C9orf72 Protein Amyotrophic Lateral Sclerosis Dipeptides Articles General Medicine medicine.disease Frontal Lobe DNA-Binding Proteins HEK293 Cells Toxicity Ran Erratum 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics Hum Mol Genet |
| ISSN: | 0964-6906 |
| Popis: | An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culture model activates programmed cell death and TDP-43 cleavage in a dose-dependent manner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being the most toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a key mediator of cytotoxicity and that cross-talk between DPR proteins likely modifies their pathogenic status in C9ALS/FTD. |
| Databáze: | OpenAIRE |
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