Flavones provide resistance to DUX4-induced toxicity via an mTor-independent mechanism
Facioscapulohumeral muscular dystrophy (FSHD) is among the most common of the muscular dystrophies, affecting nearly 1 in 8000 individuals, and is a cause of profound disability. Genetically, FSHD is linked to the contraction and/or epigenetic de-repression of the D4Z4 repeat array on chromosome 4, thereby allowing expression of the DUX4 gene in skeletal muscle. If the DUX4 transcript incorporates a stabilizing polyadenylation site the myotoxic DUX4 protein will be synthesized, resulting in muscle wasting. The mechanism of toxicity remains unclear, as many DUX4-induced cytopathologies have been described, however cell death does primarily occur through caspase 3/7-dependent apoptosis. To date, most FSHD therapeutic development has focused on molecular methods targeting DUX4 expression or the DUX4 transcript, while therapies targeting processes downstream of DUX4 activity have received less attention. Several studies have demonstrated that inhibition of multiple signal transduction pathways can ameliorate DUX4-induced toxicity, and thus compounds targeting these pathways have the potential to be developed into FSHD therapeutics. To this end, we have screened a group of small molecules curated based on their reported activity in relevant pathways and/or structural relationships with known toxicity-modulating molecules. We have identified a panel of five compounds that function downstream of DUX4 activity to inhibit DUX4-induced toxicity. Unexpectedly, this effect was mediated through an mTor-independent mechanism that preserved expression of ULK1 and correlated with an increase in a marker of active cellular autophagy. This identifies these flavones as compounds of interest for therapeutic development, and potentially identifies the autophagy pathway as a target for therapeutics.
| Errataetall: |
UpdateIn: Cell Death Dis. 2023 Nov 16;14(11):749. - PMID 37973788 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
Research square - (2023) vom: 02. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cohen, Justin [VerfasserIn] |
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| Links: |
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Date Revised 25.01.2024 published: Electronic UpdateIn: Cell Death Dis. 2023 Nov 16;14(11):749. - PMID 37973788 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.21203/rs.3.rs-2452222/v1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352878606 |
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| 500 | |a UpdateIn: Cell Death Dis. 2023 Nov 16;14(11):749. - PMID 37973788 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Facioscapulohumeral muscular dystrophy (FSHD) is among the most common of the muscular dystrophies, affecting nearly 1 in 8000 individuals, and is a cause of profound disability. Genetically, FSHD is linked to the contraction and/or epigenetic de-repression of the D4Z4 repeat array on chromosome 4, thereby allowing expression of the DUX4 gene in skeletal muscle. If the DUX4 transcript incorporates a stabilizing polyadenylation site the myotoxic DUX4 protein will be synthesized, resulting in muscle wasting. The mechanism of toxicity remains unclear, as many DUX4-induced cytopathologies have been described, however cell death does primarily occur through caspase 3/7-dependent apoptosis. To date, most FSHD therapeutic development has focused on molecular methods targeting DUX4 expression or the DUX4 transcript, while therapies targeting processes downstream of DUX4 activity have received less attention. Several studies have demonstrated that inhibition of multiple signal transduction pathways can ameliorate DUX4-induced toxicity, and thus compounds targeting these pathways have the potential to be developed into FSHD therapeutics. To this end, we have screened a group of small molecules curated based on their reported activity in relevant pathways and/or structural relationships with known toxicity-modulating molecules. We have identified a panel of five compounds that function downstream of DUX4 activity to inhibit DUX4-induced toxicity. Unexpectedly, this effect was mediated through an mTor-independent mechanism that preserved expression of ULK1 and correlated with an increase in a marker of active cellular autophagy. This identifies these flavones as compounds of interest for therapeutic development, and potentially identifies the autophagy pathway as a target for therapeutics | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Huang, Shushu |e verfasserin |4 aut | |
| 700 | 1 | |a Koczwara, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Woodman, Keryn |e verfasserin |4 aut | |
| 700 | 1 | |a Lek, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Arbiser, Jack |e verfasserin |4 aut | |
| 700 | 1 | |a Lek, Monkol |e verfasserin |4 aut | |
| 700 | 1 | |a DeSimone, Alec |e verfasserin |4 aut | |
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