Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress
Abstract Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and driver...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809423 |
| _version_ | 1797282280085913600 |
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| author | Thomas Westergard Kevin McAvoy Katelyn Russell Xinmei Wen Yu Pang Brandie Morris Piera Pasinelli Davide Trotti Aaron Haeusler |
| author_facet | Thomas Westergard Kevin McAvoy Katelyn Russell Xinmei Wen Yu Pang Brandie Morris Piera Pasinelli Davide Trotti Aaron Haeusler |
| author_sort | Thomas Westergard |
| collection | DOAJ |
| description | Abstract Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated‐PERK and the phosphorylated‐eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR‐dependent disease pathogenesis in NRE‐linked diseases. |
| first_indexed | 2024-03-07T17:10:34Z |
| format | Article |
| id | doaj.art-357cba24d5134eb4b3da6cedf90a1fe5 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:10:34Z |
| publishDate | 2019-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-357cba24d5134eb4b3da6cedf90a1fe52024-03-03T01:06:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-02-01112n/an/a10.15252/emmm.201809423Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stressThomas Westergard0Kevin McAvoy1Katelyn Russell2Xinmei Wen3Yu Pang4Brandie Morris5Piera Pasinelli6Davide Trotti7Aaron Haeusler8Department of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USADepartment of Neuroscience Jefferson Weinberg ALS Center Vickie and Jack Farber Institute for Neuroscience Jefferson University Philadelphia PA USAAbstract Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated‐PERK and the phosphorylated‐eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR‐dependent disease pathogenesis in NRE‐linked diseases.https://doi.org/10.15252/emmm.201809423ALSC9orf72DPRexcitotoxicityFTD |
| spellingShingle | Thomas Westergard Kevin McAvoy Katelyn Russell Xinmei Wen Yu Pang Brandie Morris Piera Pasinelli Davide Trotti Aaron Haeusler Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress EMBO Molecular Medicine ALS C9orf72 DPR excitotoxicity FTD |
| title | Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress |
| title_full | Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress |
| title_fullStr | Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress |
| title_full_unstemmed | Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress |
| title_short | Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress |
| title_sort | repeat associated non aug translation in c9orf72 als ftd is driven by neuronal excitation and stress |
| topic | ALS C9orf72 DPR excitotoxicity FTD |
| url | https://doi.org/10.15252/emmm.201809423 |
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