Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans
Neurodegenerative disorders (ND) like Alzheimer's (AD), Parkinson's (PD), Huntington's or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Research
2020
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| _version_ | 1826262744909742080 |
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| author | Pretsch, D Rollinger, JM Schmid, A Genov, M Wöhrer, T Krenn, L Moloney, M Kasture, A Hummel, T Pretsch, A |
| author_facet | Pretsch, D Rollinger, JM Schmid, A Genov, M Wöhrer, T Krenn, L Moloney, M Kasture, A Hummel, T Pretsch, A |
| author_sort | Pretsch, D |
| collection | OXFORD |
| description | Neurodegenerative disorders (ND) like Alzheimer's (AD), Parkinson's (PD), Huntington's or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the 'metal hypothesis of Alzheimer's disease' that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO4, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity. |
| first_indexed | 2024-03-06T19:40:55Z |
| format | Journal article |
| id | oxford-uuid:20a462c7-f071-4672-a454-00c7245b9e51 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:40:55Z |
| publishDate | 2020 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:20a462c7-f071-4672-a454-00c7245b9e512022-03-26T11:28:43ZProlongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegansJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:20a462c7-f071-4672-a454-00c7245b9e51EnglishSymplectic ElementsNature Research2020Pretsch, DRollinger, JMSchmid, AGenov, MWöhrer, TKrenn, LMoloney, MKasture, AHummel, TPretsch, ANeurodegenerative disorders (ND) like Alzheimer's (AD), Parkinson's (PD), Huntington's or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the 'metal hypothesis of Alzheimer's disease' that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO4, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity. |
| spellingShingle | Pretsch, D Rollinger, JM Schmid, A Genov, M Wöhrer, T Krenn, L Moloney, M Kasture, A Hummel, T Pretsch, A Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans |
| title | Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans |
| title_full | Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans |
| title_fullStr | Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans |
| title_full_unstemmed | Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans |
| title_short | Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans |
| title_sort | prolongation of metallothionein induction combats ass and α synuclein toxicity in aged transgenic caenorhabditis elegans |
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