Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissionsoup.com..
Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.
| Errataetall: |
CommentIn: Brain. 2021 Jun 22;144(5):1286-1288. - PMID 33712815 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:144 |
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| Enthalten in: |
Brain : a journal of neurology - 144(2021), 5 vom: 22. Juni, Seite 1467-1481 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rebelo, Adriana P [VerfasserIn] |
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| Links: |
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| Themen: |
Ataxia |
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| Anmerkungen: |
Date Completed 23.09.2021 Date Revised 23.09.2021 published: Print CommentIn: Brain. 2021 Jun 22;144(5):1286-1288. - PMID 33712815 Citation Status MEDLINE |
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| doi: |
10.1093/brain/awab071 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia |
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| 500 | |a CommentIn: Brain. 2021 Jun 22;144(5):1286-1288. - PMID 33712815 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissionsoup.com. | ||
| 520 | |a Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Guillot-Noel, Léna |e verfasserin |4 aut | |
| 700 | 1 | |a Pereira, Claudia V |e verfasserin |4 aut | |
| 700 | 1 | |a Timmann, Dagmar |e verfasserin |4 aut | |
| 700 | 1 | |a Traschütz, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Schöls, Ludger |e verfasserin |4 aut | |
| 700 | 1 | |a Coarelli, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Durr, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Anheim, Mathieu |e verfasserin |4 aut | |
| 700 | 1 | |a Tranchant, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a van de Warrenburg, Bart |e verfasserin |4 aut | |
| 700 | 1 | |a Guissart, Claire |e verfasserin |4 aut | |
| 700 | 1 | |a Koenig, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Howell, Jack |e verfasserin |4 aut | |
| 700 | 1 | |a Moraes, Carlos T |e verfasserin |4 aut | |
| 700 | 1 | |a Schenck, Annette |e verfasserin |4 aut | |
| 700 | 1 | |a Stevanin, Giovanni |e verfasserin |4 aut | |
| 700 | 1 | |a Züchner, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Synofzik, Matthis |e verfasserin |4 aut | |
| 700 | 0 | |a PREPARE network |e verfasserin |4 aut | |
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