Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

Arslanbaeva, Liaisan; Bisaglia, Marco

doi:10.3390/molecules27051471

Cited by 9 publications

(6 citation statements)

References 122 publications

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“…Additionally, FGF1 is expressed by cholinergic neurons in the anterior horn of the human spinal cord, and the number of FGF1-positive neurons and the level of FGF1 expression are considerably lower in the anterior horn of the spinal cord in patients with ALS than in controls 38 . FGF1 activates Nrf2 in astrocytes, which has also been shown to be beneficial for neuronal survival by regulating the expression of genes that protect against oxidative stress 39 40. These findings suggest that FGF1 may have a beneficial effect on the survival of patients with ALS and may be a therapeutic target to improve prognosis.…”

Section: Discussionmentioning

confidence: 93%

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Nakamura

Tohnai

Nakatochi

et al. 2023

J Neurol Neurosurg Psychiatry

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BackgroundSeveral genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS.MethodsWe enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS.ResultsThree novel loci were significantly associated with the survival of patients with sporadic ALS—FGF1at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10−9),THSD7Aat 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10−8) andLRP1at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10−8).FGF1andTHSD7Avariants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression ofFGF1andTHSD7Awas partially disrupted. The rs60565245 was not associated withLRP1mRNA expression.ConclusionsWe identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression ofFGF1andTHSD7Aand the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

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Section: Discussionmentioning

confidence: 93%

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Nakamura

Tohnai

Nakatochi

et al. 2023

J Neurol Neurosurg Psychiatry

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“…Being responsible for the regulation of the basal and induced expression of multiple antioxidant response-element-dependent genes, NRF2 controls the pathophysiological outcomes of the exposure to ROS [ 38 ]. Furthermore, the activation of the NRF2 pathway was studied as a potential treatment approach for amyotrophic lateral sclerosis, in which motor neurons progressively degenerate due to their vulnerability to oxidative stress [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotective and Antioxidant Effects of Nanocurcumin Oral Suspension against Lipopolysaccharide-Induced Cortical Neurotoxicity in Rats

et al. 2022

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Lipopolysaccharide (LPS) proved to be an important tool, not only in the induction of neuroinflammatory models, but also in demonstrating the behavioral and cognitive consequences of endotoxemia. Curcumin, in its native form, has proven to be a worthy candidate for further development as it protects the dopaminergic neurons against LPS-induced neurotoxicity. However, it remains hindered by its poor bioavailability. In this study we aim to explore the possible molecular mechanism of LPS-induced neurotoxicity and the possible protective effects of orally supplemented nanocurcumin. Thirty-six adult male Wistar rats weighing 170–175 g were divided into six groups and treated with single I.P. (intra-peritoneal) dose of LPS (sigma and extracted; separately) (5 mg/kg BW) plus daily oral nanocurcumin (15 mg/kg BW). The rats were followed for 7 days after the LPS injection and nanocurcumin supplementations daily via oral gavage. After scarification, the levels of neurotransmitters, antioxidants, and amyloidogenesis markers were assessed in brain tissues. Nanocurcumin showed adequate antioxidant and neuroprotective effects, rescuing the rats which had been injected intraperitoneally with LPS endotoxin.

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“…It participates in the transcription of numerous genes involved in glutathione metabolism, iron homeostasis, and antioxidant response as well as in the regulation of energetic metabolism, including glycolysis, pentose phosphate pathway, fatty acid, and glutamine metabolism. Interestingly, Nrf2 expression has been described to decrease with aging, and, more importantly, the Nrf2 pathway appears to be compromised in ALS patients as well as in cell cultures and animal models of the disease [43][44][45][46].…”

Section: Dj-1 Protection Against Oxidative Stress and Mitochondrial D...mentioning

confidence: 99%

Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us

Sandrelli

Bisaglia

2023

IJMS

Self Cite

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Amyotrophic lateral sclerosis (ALS) is an adult-onset disease which causes the progressive degeneration of cortical and spinal motoneurons, leading to death a few years after the first symptom onset. ALS is mainly a sporadic disorder, and its causative mechanisms are mostly unclear. About 5–10% of cases have a genetic inheritance, and the study of ALS-associated genes has been fundamental in defining the pathological pathways likely also involved in the sporadic forms of the disease. Mutations affecting the DJ-1 gene appear to explain a subset of familial ALS forms. DJ-1 is involved in multiple molecular mechanisms, acting primarily as a protective agent against oxidative stress. Here, we focus on the involvement of DJ-1 in interconnected cellular functions related to mitochondrial homeostasis, reactive oxygen species (ROS) levels, energy metabolism, and hypoxia response, in both physiological and pathological conditions. We discuss the possibility that impairments in one of these pathways may affect the others, contributing to a pathological background in which additional environmental or genetic factors may act in favor of the onset and/or progression of ALS. These pathways may represent potential therapeutic targets to reduce the likelihood of developing ALS and/or slow disease progression.

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Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

Cited by 9 publications

References 122 publications

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

The Neuroprotective and Antioxidant Effects of Nanocurcumin Oral Suspension against Lipopolysaccharide-Induced Cortical Neurotoxicity in Rats

Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us

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