Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance
The hexanucleotide expansion of the <i>C9orf72</i> gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling...
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MDPI AG
2022-09-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/10/1897 |
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| author | José Jiménez-Villegas Janine Kirby Ana Mata Susana Cadenas Martin R. Turner Andrea Malaspina Pamela J. Shaw Antonio Cuadrado Ana I. Rojo |
| author_facet | José Jiménez-Villegas Janine Kirby Ana Mata Susana Cadenas Martin R. Turner Andrea Malaspina Pamela J. Shaw Antonio Cuadrado Ana I. Rojo |
| author_sort | José Jiménez-Villegas |
| collection | DOAJ |
| description | The hexanucleotide expansion of the <i>C9orf72</i> gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from <i>C9orf72</i> patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from <i>C9orf72</i> ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to <i>C9orf72</i> pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring <i>C9orf72</i> expansion repeats. |
| first_indexed | 2024-03-09T20:49:45Z |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T20:49:45Z |
| publishDate | 2022-09-01 |
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| series | Antioxidants |
| spelling | doaj.art-982b51010e2142f7aab11af581ca5cf82023-11-23T22:37:31ZengMDPI AGAntioxidants2076-39212022-09-011110189710.3390/antiox11101897Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway ImbalanceJosé Jiménez-Villegas0Janine Kirby1Ana Mata2Susana Cadenas3Martin R. Turner4Andrea Malaspina5Pamela J. Shaw6Antonio Cuadrado7Ana I. Rojo8Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), 28029 Madrid, SpainSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UKCentro de Biología Molecular “Severo Ochoa” (CSIC/UAM), 28049 Madrid, SpainCentro de Biología Molecular “Severo Ochoa” (CSIC/UAM), 28049 Madrid, SpainNuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UKNeuroscience and Trauma Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London E1 2AT, UKSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UKDepartment of Biochemistry, Medical College, Autonomous University of Madrid (UAM), 28029 Madrid, SpainDepartment of Biochemistry, Medical College, Autonomous University of Madrid (UAM), 28029 Madrid, SpainThe hexanucleotide expansion of the <i>C9orf72</i> gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from <i>C9orf72</i> patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from <i>C9orf72</i> ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to <i>C9orf72</i> pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring <i>C9orf72</i> expansion repeats.https://www.mdpi.com/2076-3921/11/10/1897NRF2amyotrophic lateral sclerosis<i>C9orf72</i>dipeptide repeat proteins |
| spellingShingle | José Jiménez-Villegas Janine Kirby Ana Mata Susana Cadenas Martin R. Turner Andrea Malaspina Pamela J. Shaw Antonio Cuadrado Ana I. Rojo Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance Antioxidants NRF2 amyotrophic lateral sclerosis <i>C9orf72</i> dipeptide repeat proteins |
| title | Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance |
| title_full | Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance |
| title_fullStr | Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance |
| title_full_unstemmed | Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance |
| title_short | Dipeptide Repeat Pathology in <i>C9orf72</i>-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance |
| title_sort | dipeptide repeat pathology in i c9orf72 i als is associated with redox mitochondrial and nrf2 pathway imbalance |
| topic | NRF2 amyotrophic lateral sclerosis <i>C9orf72</i> dipeptide repeat proteins |
| url | https://www.mdpi.com/2076-3921/11/10/1897 |
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