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

Jiménez-Villegas, José; Kirby, Janine; Mata, Ana; Cadenas, Susana; Turner, Martin R.; Malaspina, Andrea; Shaw, Pamela J.; Cuadrado, Antonio; Rojo, Ana I.

doi:10.3390/antiox11101897

Cited by 9 publications

(13 citation statements)

References 54 publications

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“…While some studies have reported the Nrf2 pathway to be disrupted in ALS patient samples (60)(61)(62), very limited data exists on C9orf72-related ALS samples. Recently, Jimenez-Villegas et al (63) have shown that Nrf2 activation is impaired in cell culture models of arginine-DPR toxicity, where they also saw an improvement in cell viability upon treatment with DMF. We have extended these findings showing the benefit of targeting Keap1/Nrf2 in vivo as well as patient-derived iNeurons which further emphasises the importance of Nrf2 activation as a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons

Au,

Miller-Fleming,

Sanchez-Martinez

et al. 2023

Preprint

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Mitochondrial dysfunction such as excess production of reactive oxygen species (ROS) and defective mitochondrial dynamics are common features ofC9orf72Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD), but it remains unclear whether these are causative or a consequence of the pathogenic process. To address this, we have performed a comprehensive characterisation of mitochondrial dysfunctionin vivomodel, analysing multiple transgenicDrosophilamodels ofC9orf72-related pathology, which can be correlated to disease-relevant locomotor deficits. Genetic manipulations to reverse different aspects of mitochondrial disruption revealed that only genetic upregulation of antioxidants such as mitochondrial Sod2 and catalase were able to rescueC9orf72locomotor deficits, suggesting a causative link between mitochondrial dysfunction, ROS and behavioural phenotypes. By analysing the Keap1/Nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, a central antioxidant response pathway, we observed a blunted response in theC9orf72models. However, both genetic reduction of Keap1 and its pharmacological targeting by dimethyl fumarate (DMF), was able to rescueC9orf72-related motor deficits. In addition, analysis ofC9orf72patient-derived iNeurons showed increased ROS that was suppressed by DMF treatment. These results indicate that mitochondrial oxidative stress is an upstream pathogenic mechanism leading to downstream mitochondrial dysfunction such as alterations in mitochondrial function and turnover. Consequently, our data support targeting the Keap1/Nrf2 signalling pathway as a viable therapeutic strategy forC9orf72-related ALS/FTD.

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Section: Discussionmentioning

confidence: 99%

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons

Au,

Miller-Fleming,

Sanchez-Martinez

et al. 2023

Preprint

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“…Onesto et al report an increase in ROS levels in cells expressing mutated C9orf72 altering mitochondrial activity and might be the mechanism behind the cell death observed in ALS (Onesto et al, 2016). Moreover, the expression of redox genes was also observed to be impaired in ALS, where expression of the master regulator of redox genes, i.e., NRF2, is also reported to decrease in cells expressing DPRs (Jimenez-Villegas et al, 2022). On the other hand, the loss of C9orf72 functions is also linked with mitochondrial abnormalities, where C9orf72 controls assembly of complex-I, maintaining OXPHOS.…”

Section: Deciphering the Link Between Amyotrophic Lateral Sclerosis A...mentioning

confidence: 99%

Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

Jagtap

Kumar

Kinger

et al. 2023

Front. Cell Dev. Biol.

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The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Alzheimer’s disease, along with protein misfolding. The aberrantly folded proteins are known to link with impaired mitochondrial pathways, further contributing to disease pathogenesis. Despite their central significance, the implications of mitochondrial homeostasis disruption on other organelles and cellular processes remain insufficiently explored. Here, we have reviewed the dysfunction in mitochondrial physiology, under neuron degenerating conditions. The disease misfolded proteins impact quality control mechanisms of mitochondria, such as fission, fusion, mitophagy, and proteasomal clearance, to the detriment of neuron. The adversely affected mitochondrial functional roles, like oxidative phosphorylation, calcium homeostasis, and biomolecule synthesis as well as its axes and contacts with endoplasmic reticulum and lysosomes are also discussed. Mitochondria sense and respond to multiple cytotoxic stress to make cell adapt and survive, though chronic dysfunction leads to cell death. Mitochondria and their proteins can be candidates for biomarkers and therapeutic targets. Investigation of internetworking between mitochondria and neurodegeneration proteins can enhance our holistic understanding of such conditions and help in designing more targeted therapies.

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“…However, signs of OS, including protein and lipid peroxidation, were found in non-mutated ALS cases as well [ 131 , 132 , 133 ] and were associated with a decrease in antioxidant enzymes’ activity and with a possible pro-oxidative state [ 134 ].…”

Section: Oxidative Stress and Inflammation In Alsmentioning

confidence: 99%

New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases

Scarian,

Viola,

Dragoni

et al. 2024

IJMS

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Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.

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

Cited by 9 publications

References 54 publications

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons

Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases

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