Aug 2026· Frontiers in Pharmacology· Vol 17· 0 citations· 29 references
Medicine
TL;DR
Findings support the protective potential of RTA-408 in SCA3-related models and show its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes.
Abstract
Introduction Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3). Mutant ataxin-3 accumulation, oxidative stress, mitochondrial dysfunction, and impaired protein quality control contribute to its pathogenesis; however, no disease-modifying therapy is currently available. Omaveloxolone (RTA-408), an activator of nuclear factor erythroid 2–related factor 2 (Nrf2), is approved for Friedreich’s ataxia, but its therapeutic potential in SCA3 remains unclear. Methods We evaluated the effects of RTA-408 in MJD78 cells and Drosophila SCA3 models. Cell viability, apoptosis, mutant ataxin-3 levels, Nrf2-associated antioxidant proteins, p62/autophagy-related markers, and mitochondrial phenotypes were assessed in MJD78 cells. Survival, climbing ability, and external eye degeneration were evaluated in SCA3tr-Q78 flies. Results In MJD78 cells, 0.3 and 0.5 μM RTA-408 more consistently improved cell viability, reduced apoptosis, and decreased detectable mutant ataxin-3 accumulation than 0.1 μM RTA-408. RTA-408 increased the nuclear-to-cytoplasmic Nrf2 ratio and upregulated NQO1, HO-1, and SOD2 without significantly altering intracellular or mitochondrial reactive oxygen species levels. RTA-408 also increased p62 expression, whereas ATG7, Beclin 1, LAMP2, and the LC3-II/LC3-I ratio showed limited or nonsignificant changes, indicating p62 upregulation without definitive evidence of canonical autophagic flux activation. In addition, 0.3 μM RTA-408 partially shifted mitochondrial morphology from globe-like to elongated forms and increased mitochondrial DNA copy number. In SCA3tr-Q78 flies, RTA-408 partially improved survival, locomotor performance, eye size, and pigmentation, with more evident benefits at earlier stages. Conclusion These findings support the protective potential of RTA-408 in SCA3-related models. Its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes. Further studies are needed to clarify the underlying mechanisms and determine the translational potential of RTA-408 for SCA3.
AIMS
Friedreich ataxia (FRDA) is a neurodegenerative disorder typically caused by autosomal recessive inheritance of expanded guanine-adenine-adenine (GAA) repeats (>56) in both alleles of the frataxin (FXN) gene, leading to FXN protein deficiency. Omaveloxolone (Omav) is the only approved therapy. Therefore, further therapeutic options are essential. Previously, we showed that sulforaphane (SF) increases FXN expression and modulates epigenetic, inflammatory, and oxidative stress pathways in sensory neurons from a patient induced pluripotent stem cells (iPSCs) with 550 GAA1 repeats (FA2). Here, we compared SF, Omav, and dimethyl fumarate (DMF) treatment in sensory neurons derived from three patient iPSC lines with varying GAA1 repeats: FA1 (867), FA2, and FA3 (450).
RESULTS
In FA1, SF treatment improved cell viability and reduced oxidative stress and inflammation. In FA3, SF increased cell viability, FXN protein levels, and gene and protein expression of redox markers, while targeting dysregulated epigenetic mechanisms and inflammation. All three lines showed SF's consistent anti-oxidant and anti-inflammatory effects. Responses to Omav and DMF varied across the FA lines with less pronounced effects than when treated with SF. Overall, SF was more effective than Omav and DMF in improving cell viability and regulating FXN expression and epigenetic, redox, and inflammatory pathways.
INNOVATION
These findings reveal variability in drug responses based on FRDA genetic profiles and position SF as a promising drug to address multiple pathological processes.
CONCLUSION
Our preclinical data support SF as a strong FRDA drug candidate. Clinical evaluation is warranted to confirm its full therapeutic potential. Antioxid. Redox Signal. 00, 000-000.
Wenyao Yang, Bruce Thompson, S. Miellet et al.· Antioxidants and Redox Signa...· 0 citations
It is suggested that BL-918 could potentially modulate SMP30 at the functional protein level, and SwissADME and ProTox 3.0 characterized BL-918 as a viable therapeutic lead, outlining key pharmacokinetic targets for future optimization.
Hardi M. Makwana, S. S. Swain, B. Paital et al.· Journal of Applied Pharmaceu...· 0 citations
Oxidative stress is widely accepted as one of the important factors contributing to neurodegeneration, leading to fatal neurodegenerative diseases (NDD) such as Amyotrophic Lateral Sclerosis. Since flavonoids possess antioxidant properties, we investigated whether Fisetin (FS) and Quercetin (QR) protected cells from oxidative stress arising from pathogenic mutations G262R (G > A) and P438L (C > T) of SQSTM1 found in Indian ALS patients. SQSTM1 codes for p62 protein and is involved in multiple signaling pathways through its various domains. We studied changes in cell viability and cellular functions using immunoblotting, confocal microscopy, immunoprecipitation and FACS analysis in the presence and absence of FS and QR. Supplementation with FS and QR in SH-SY5Y cells expressing SQS-wild type and mutants increased cell viability and decreased ROS formation. Also, Nrf2 protein levels increased to offset oxidative stress response. In addition, we studied the effect of FS on the nuclear-cytoplasmic distribution of TDP-43 protein, which serves as a hallmark for ALS. FS corrected the nuclear-cytoplasm translocation of TDP-43 protein and decreased late apoptosis in mutants. Our study illustrates that both FS and QR shield cells from oxidative stress, and that FS imparted better protection against the pathogenic effect of SQSTM1 mutants in SH-SY5Y neuronal cells.
Nidhi Singh, James Gomes· Toxicology and Applied Pharm...· 0 citations
INTRODUCTION
HD is a hereditary neurodegenerative disease caused by the amplification of the CAG trinucleotide repeat in the HTT gene, leading to a Mutant Huntingtin (mHTT) protein that dysregulates transcription, promotes protein aggregation, induces neuroinflammation, and impairs mitochondrial function. Motor dysfunction, cognitive decline, and mental disorders are manifestations of these biochemical abnormalities. Effective disease-modifying treatments are still limited, even with recent improvements. This review investigates the increasing relevance of Klotho, an anti-aging protein with neuroprotective, antioxidant, and anti-inflammatory characteristics, as a possible therapeutic target in Huntington disease.
METHODS
We did a comprehensive literature search across PubMed, Scopus, and Web of Science databases. Klotho's molecular functions in neural protection, energy metabolism, oxidative stress reduction, and anti-inflammatory signalling were investigated in the context of HD pathogenesis.
RESULTS
Klotho appears to influence critical neurodegenerative processes involved in HD. It inhibits NF-κB and NLRP3 inflammasome activity, stimulates antioxidant enzyme expression (SOD, catalase), promotes GluN2B-NMDA receptor-mediated synaptic plasticity, and increases astrocytic aerobic glycolysis via FGFR1-ERK signaling. These functions may mitigate mHTT- induced neuronal damage. Pharmacologic treatments (e.g., PPAR-γ agonists), vitamin D, and lifestyle interventions can all modulate klotho expression.
DISCUSSION
Klotho exhibits neuroprotective effects in Huntington's disease by reducing NF-κB/NLRP3- mediated inflammation, strengthening antioxidant defenses, promoting GluN2B-NMDA- dependent synaptic plasticity, and improving astrocytic metabolic support via FGFR1-ERK signaling. One intriguing treatment approach for mutant huntingtin-induced neurotoxicity is the modification of klotho expression.
CONCLUSION
Klotho is a promising neurochemical modulator with disease-modifying properties in HD. Its multifunctional protective activities are consistent with important pathological markers of HD, necessitating more preclinical and clinical studies to confirm its translational value.
Shikha Singh, Avnesh Kumar, Falguni Goel et al.· Current molecular medicine· 0 citations
Alzheimer’s disease (AD) is a neurodegenerative disorder, which is characterized by several features, such as the deposition of amyloid β (Aβ) fibrils in the brain, leading to the formation of plaques and secondly tau-associated neurofibrillary tangles, resulting in the degeneration of the brain cells. Another feature of AD is mitochondrial dysfunction and oxidative stress, which are linked to the excessive production of reactive oxygen species (ROS). Under physiological conditions, ROS homeostasis is well controlled by the ROS generating system and the cellular antioxidant network. This antioxidant network is in part controlled by nuclear factor erythroid 2-related factor 2 (Nrf2), and its activation protects tissues against oxidative stress and chronic inflammation. Since oxidative stress, inflammation, and impaired proteostasis are significantly involved in the pathogenesis of AD, the KEAP1-Nrf2 system has emerged as a promising therapeutic target for the disease. Caenorhabditis elegans is an invaluable model organism among others for neurodegenerative disease research, due to its short life cycle, transparent body, and fully mapped nervous system and many transgenic C. elegans models have been developed to study different aspects of AD. This review attempts to provide comprehensive understanding of the molecular characteristics and pathological basis of AD, including the altered Nrf2-ARE signaling in AD and the molecular architecture and regulation of the Nrf2-SKN-1 pathway in C. elegans. An overview of plant-derived natural products and their effect on Nrf2/SKN-1 activation. Several classical and novel transgenic strains are described, translating findings from C. elegans to mammalian models and humans, including clinical translations and ongoing trials, as well as personalized medicinal approaches are discussed.
A. Bellver-Sanchis, N. Ralchev, Patrizia R. Romanska et al.· International Journal of Mol...· 0 citations
It is shown that microglia generated from FRDA patient-derived iPSCs exhibit a cell-autonomous pro-inflammatory phenotype in the absence of exogenous inflammatory stimuli.
Ye-Man Tang, Rita Lo, Louise Thiry et al.· bioRxiv· 0 citations
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