Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons DOI Creative Commons
Wing Hei Au, Leonor Miller‐Fleming, Álvaro Sánchez-Martínez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 2, 2023

Abstract Mitochondrial dysfunction such as excess production of reactive oxygen species (ROS) and defective mitochondrial dynamics are common features C9orf72 Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD), but it remains unclear whether these causative or a consequence the pathogenic process. To address this, we have performed comprehensive characterisation in vivo model, analysing multiple transgenic Drosophila models -related pathology, which can be correlated to disease-relevant locomotor deficits. Genetic manipulations reverse different aspects disruption revealed that only genetic upregulation antioxidants Sod2 catalase were able rescue deficits, suggesting link between dysfunction, ROS behavioural phenotypes. By Keap1/Nuclear factor erythroid 2–related 2 (Nrf2) pathway, central antioxidant response observed blunted models. However, both reduction Keap1 its pharmacological targeting by dimethyl fumarate (DMF), was motor In addition, analysis patient-derived iNeurons showed increased suppressed DMF treatment. These results indicate oxidative stress is an upstream mechanism leading downstream alterations function turnover. Consequently, our data support Keap1/Nrf2 signalling pathway viable therapeutic strategy for ALS/FTD.

Language: Английский

Autophagy in Parkinson’s Disease DOI Creative Commons

Lior Nechushtai,

Dan Frenkel, Ronit Pinkas‐Kramarski

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1435 - 1435

Published: Sept. 22, 2023

Parkinson’s disease (PD) is a devastating associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the protein aggregates, damaged unneeded proteins, organelles, allowing their clearance, thereby maintaining cell homeostasis. Impaired autophagy cause abnormal proteins. Incomplete or impaired explain neurotoxic aggregates several Indeed, have suggested contribution α-Syn accumulation, death neuroinflammation. In this review, we summarize recent literature on involvement pathogenesis.

Language: Английский

Citations

34
Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases DOI Creative Commons
Siwei Chu,

Xinyi Xie,

Carla Payan

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Aug. 7, 2023

Abstract The AAA + ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, disease conditions. A number mutations have revealed importance human health. In particular, facilitates dismantling aggregates removal dysfunctional organelles. These are critical events prevent malfunction brain other parts line this idea, mutants linked onset progression neurodegeneration diseases. intricate molecular mechanisms that connect distinct pathologies continue be uncovered. Emerging evidence supports model controls cellular functions on multiple levels type specific fashion. Accordingly, derail homeostasis through several can instigate disease. Our review focuses association between neurodegeneration. We discuss latest insights field, emphasize open questions, speculate potential as drug target some most devastating forms

Language: Английский

Citations

15
A Proteomic Approach Identified TFEB as a Key Player in the Protective Action of Novel CB2R Bitopic Ligand FD22a against the Deleterious Effects Induced by β-Amyloid in Glial Cells DOI Creative Commons
Beatrice Polini, Lorenzo Zallocco, Francesca Gado

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 875 - 875

Published: May 19, 2024

Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration multifaceted nature NDDs, development multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target cannabinoid receptor type II (CB2R) rapidly emerging novel effective MTDLs against such Alzheimer's disease (AD). We recently developed first CB2R bitopic/dualsteric ligand, namely FD22a, which revealed ability to induce neuroprotection with fewer side effects. To explore potential FD22a a multitarget drug for treatment we investigated here its prevent toxic effect β-amyloid (Aβ

Language: Английский

Citations

5
Neuroprotective effects and possible mechanisms of berberine in animal models of Alzheimer’s disease: a systematic review and meta-analysis DOI Creative Commons

Lijuan Dan,

Yanwei Hao, Jiaxin Li

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

Background: Recently, multiple preclinical studies have reported the beneficial effect of berberine in treatment Alzheimer’s disease (AD). Nevertheless, neuroprotective effects and possible mechanisms against AD are not universally recognized. This study aimed to conduct a systematic review meta-analysis by integrating relevant animal assess potential on AD. Methods: We systematically searched PubMed, Embase, Scopus Web Science databases that models up 1 February 2023. The escape latency, times crossing platform, time spent target quadrant pro-oligomerized amyloid beta 42 (Aβ 1-42 ) were included as primary outcomes. secondary outcomes Tau-ps 204, 404, β-site APP cleaving enzyme (BACE1), precursor protein (APP), acetylcholine esterase (AChE), tumor necrosis factor ⍺ (TNF-α), interleukin 1β (IL-1β), IL-6, nitric oxide (NO), glial fibrillary acidic (GFAP), malonaldehyde (MDA), glutathione S-transferase (GST), (GSH), peroxidase (GPx), Beclin-1 neuronal apoptosis cells. was conducted using RevMan 5.4 STATA 15.1. SYRCLE’s risk bias tool used methodological quality. Results: Twenty-two 453 animals analysis. overall results showed significantly shortened latency ( p < 0.00001), increased platform 0.00001) decreased Aβ deposition 202 404 = 0.002), improved BACE1, APP, AChE, Beclin-1, cells, oxidative stress inflammation levels. Conclusion: Berberine may be promising drug for based evidence (especially when dose 5–260 mg/kg). these protective closely related anti-neuroinflammation, anti-oxidative stress, modulation autophagy, inhibition protection cholinergic system. However, limited quality existing research. Larger methodologically more rigorous research needed provide convincing evidence.

Language: Английский

Citations

4
C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role? DOI Creative Commons
Chantal Sellier, Philippe Corcia, Patrick Vourc’h

et al.

Revue Neurologique, Journal Year: 2024, Volume and Issue: 180(5), P. 417 - 428

Published: April 11, 2024

The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. causative mutation in C9ORF72 an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located the first intron gene. aim this review to propose a comprehensive update on recent developments clinical, biological therapeutics aspects related order highlight current understanding genotype-phenotype correlations, also machinery leading neuronal death. We will particularly focus broad phenotypic presentation C9ORF72-related diseases, that goes well beyond classical phenotypes observed ALS FTD patients. Last, we comment possible therapeutical hopes for patients carrying HRE.

Language: Английский

Citations

4
Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes inC9orf72ALS/FTD models DOI Creative Commons
Wing Hei Au, Leonor Miller‐Fleming, Álvaro Sánchez-Martínez

et al.

Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(9), P. e202402853 - e202402853

Published: June 21, 2024

Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this cause or consequence the pathogenic process. Analysing multiple aspects mitochondrial biology across several Drosophila models -ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss locomotor performance. Notably, only genetic manipulations that reversed stress levels were also able to rescue deficits, supporting causative link between dysfunction, behavioural phenotypes. Targeting key antioxidant Keap1/Nrf2 pathway, reduction Keap1 pharmacological inhibition by dimethyl fumarate significantly rescued -related motor deficits. Finally, ROS elevated in patient-derived iNeurons effectively suppressed treatment. These results indicate an important mechanistic contributor pathogenesis, affecting function turnover. signalling pathway combat represents therapeutic strategy for ALS/FTD.

Language: Английский

Citations

4
Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer’s, Parkinson’s, and ALS DOI Open Access
Corneliu Toader,

Călin Petru Tătaru,

Octavian Munteanu

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12613 - 12613

Published: Nov. 24, 2024

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene these once-intractable conditions. This review synthesizes the latest insights into underlying dynamics neurodegeneration, revealing how intertwined pathways drive course diseases. With an eye on most promising advances, we explore innovative therapies emerging cutting-edge research: nanotechnology-based drug delivery systems capable navigating blood-brain barrier, gene-editing tools like CRISPR designed correct harmful variants, stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored align individual profiles, while diagnostics biomarkers ushering era early, precise disease detection. Furthermore, novel perspectives gut-brain axis sparking interest mounting evidence suggests microbiome modulation may play role reducing neuroinflammatory responses linked neurodegenerative progression. Taken together, advances signal shift toward comprehensive, personalized approach could transform care. By integrating techniques, this offers forward-looking perspective future where treatments aim just manage symptoms fundamentally alter progression, presenting renewed hope for improved patient outcomes.

Language: Английский

Citations

4
Regulation of physiological and pathological condensates by molecular chaperones DOI Creative Commons

Nadeen Akaree,

Valentina Secco,

Flonia Levy‐Adam

et al.

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the response and various diseases. SGs, composed several hundred RNA‐binding proteins, form transiently protect mRNAs from translation disassemble when subsides. Interestingly, SGs contain aggregation‐prone such as TDP‐43, FUS, hnRNPA1, others, which typically found pathological inclusions seen autopsy tissues amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) patients. Moreover, mutations these genes lead familial ALS FTD. This led researchers propose aggregation is seeded by aberrant SGs: fail properly disassemble, lose their properties, become finally ‘mature’ into aggregates. Here, we discuss evidence supporting this model for ALS/FTD‐associated proteins. We further continue focus on molecular chaperone‐mediated regulation one hand, other. In addition review ALS/FTD‐relevant nuclear condensates, namely paraspeckles, anisosomes, nucleolar amyloid bodies, emerging chaperones. As majority chaperoning mechanisms disassembly, highlight parallel themes condensation across different chaperone families, underscoring potential early disease intervention.

Language: Английский

Citations

0
The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) DOI Creative Commons
Jimmy Beckers, Philip Van Damme

Autophagy Reports, Journal Year: 2025, Volume and Issue: 4(1)

Published: March 20, 2025

Language: Английский

Citations

0
Neuroprotective effects of punicalagin and/or micronized zeolite clinoptilolite on manganese‐induced Parkinson's disease in a rat model: Involvement of multiple pathways DOI Creative Commons
Karema Abu‐Elfotuh,

Ashwaq N. Abbas,

Mazin A. A. Najm

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(10)

Published: Oct. 1, 2024

Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl

Language: Английский

Citations

3