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Antioxidants
Volume 11
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10.3390/antiox11101897
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Article

Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance

by
José Jiménez-Villegas
1,2,3,4,
Janine Kirby
5,
Ana Mata
6,7,
Susana Cadenas
6,7,
Martin R. Turner
8,
Andrea Malaspina
9,10,
Pamela J. Shaw
5,
Antonio Cuadrado
1,2,3,4 and
Ana I. Rojo
1,2,3,4,*
1
Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), 28029 Madrid, Spain
2
Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC/UAM), 28029 Madrid, Spain
3
Instituto de Investigación Sanitaria La Paz (IdiPaz), 28029 Madrid, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid, Spain
5
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
6
Centro de Biología Molecular “Severo Ochoa” (CSIC/UAM), 28049 Madrid, Spain
7
Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain
8
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
9
Neuroscience and Trauma Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London E1 2AT, UK
10
Queen Square Motor Neuron Disease Centre, Neuromuscular Department, Institute of Neurology, University College London, London WC1N 3BG, UK
*
Author to whom correspondence should be addressed.
Antioxidants 2022, 11(10), 1897; https://doi.org/10.3390/antiox11101897
Submission received: 23 August 2022 / Revised: 19 September 2022 / Accepted: 21 September 2022 / Published: 25 September 2022
(This article belongs to the Special Issue Molecular Targets of Oxidative Stress: Focus on the Nrf2 Signaling Pathway in Health and Disease)
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Abstract

The hexanucleotide expansion of the C9orf72 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 C9orf72 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 C9orf72 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 C9orf72 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 C9orf72 expansion repeats.
Keywords: NRF2; amyotrophic lateral sclerosis; C9orf72; dipeptide repeat proteins NRF2; amyotrophic lateral sclerosis; C9orf72; dipeptide repeat proteins

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MDPI and ACS Style

Jiménez-Villegas, J.; Kirby, J.; Mata, A.; Cadenas, S.; Turner, M.R.; Malaspina, A.; Shaw, P.J.; Cuadrado, A.; Rojo, A.I. Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance. Antioxidants 2022, 11, 1897. https://doi.org/10.3390/antiox11101897

AMA Style

Jiménez-Villegas J, Kirby J, Mata A, Cadenas S, Turner MR, Malaspina A, Shaw PJ, Cuadrado A, Rojo AI. Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance. Antioxidants. 2022; 11(10):1897. https://doi.org/10.3390/antiox11101897

Chicago/Turabian Style

Jiménez-Villegas, José, Janine Kirby, Ana Mata, Susana Cadenas, Martin R. Turner, Andrea Malaspina, Pamela J. Shaw, Antonio Cuadrado, and Ana I. Rojo. 2022. "Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance" Antioxidants 11, no. 10: 1897. https://doi.org/10.3390/antiox11101897

APA Style

Jiménez-Villegas, J., Kirby, J., Mata, A., Cadenas, S., Turner, M. R., Malaspina, A., Shaw, P. J., Cuadrado, A., & Rojo, A. I. (2022). Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance. Antioxidants, 11(10), 1897. https://doi.org/10.3390/antiox11101897

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