Role and mechanism of ferroptosis in neurological diseases

Molecular Metabolism, Journal Year: 2022, Volume and Issue: 61, P. 101502 - 101502

Published: April 19, 2022

Ferroptosis, as a new form of cell death, is different from other deaths such autophagy or senescence. Ferroptosis involves in the pathophysiological progress several diseases, including cancers, cardiovascular nervous system and kidney damage. Since oxidative stress iron deposition are broad pathological features neurological role ferroptosis diseases has been widely explored. mainly characterized by changes homeostasis, iron-dependent lipid peroxidation, glutamate toxicity accumulation, which can be specifically reversed inducers inhibitors. The regulated metabolism iron, lipids amino acids through System Xc−, voltage-dependent anion channels, p53, p62-Keap1-Nrf2, mevalonate pathways. This review also focus on regulatory pathways its research diseases. current researches mostly key ferroptosis. At same time, was found playing bidirectional regulation Therefore, specific mechanisms still need to further explored provide perspectives for application treatment

Language: Английский

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Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(11), P. 2866 - 2884

Published: Oct. 9, 2023

Abstract Huntington’s disease (HD) is a devastating monogenic neurodegenerative characterized by early, selective pathology in the basal ganglia despite ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to development early cognitive phenotypes are poorly understood. Here we show that there loss synaptic connections between cortex striatum postmortem tissue from patients with HD associated increased activation localization complement proteins, innate immune molecules, elements. We also found levels secreted molecules elevated cerebrospinal fluid premanifest correlate established measures burden. In preclinical genetic models HD, proteins mediate elimination corticostriatal synapses at an stage pathogenesis, marking them for removal microglia, brain’s resident macrophage population. This process requires huntingtin be expressed both cortical striatal neurons. Inhibition complement-dependent mechanism through administration therapeutically relevant C1q function-blocking antibody or ablation receptor on microglia prevented synapse loss, excitatory input rescued visual discrimination learning flexibility deficits models. Together, our findings implicate cascade selective, presymptomatic HD; they provide new data support as therapeutic target intervention.

Language: Английский

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Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(3), P. 579 - 615

Published: Jan. 24, 2024

Abstract This article provides an overview of the background knowledge ferroptosis in nervous system, as well key role nuclear factor E2-related 2 (Nrf2) regulating ferroptosis. The takes Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS) starting point to explore close association between Nrf2 ferroptosis, which is clear significant importance for understanding mechanism neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links pathogenesis NDs. As progresses, damage antioxidant excessive OS, altered expression levels, especially inhibition by lipid peroxidation inhibitors adaptive enhancement signaling, demonstrate potential clinical significance detecting identifying targeted therapy neuronal loss mitochondrial dysfunction. These findings provide new insights possibilities treatment prevention

Language: Английский

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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 20, 2024

Abstract Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAG n ) huntingtin ( HTT gene leads to neurodegeneration after decades of apparent latency. Inherited alleles with longer CAG hasten onset; length this also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence age-at-onset. To understand relationship between cell’s CAG-repeat its state, we developed single-cell method for measuring together genome-wide RNA expression. We found expands from 40-45 CAGs 100-500+ HD-vulnerable SPNs but not other cell types, these long expansions acquired at different times by individual SPNs. Surprisingly, 40 150 had no effect upon expression – 150-500+ shared profound gene-expression changes. These involved hundreds genes, escalated alongside further expansion, eroded positive then negative features neuronal identity, culminated senescence/apoptosis genes. Rates neuron loss across stages reflected rates entered biologically distorted state. Our results suggest repeats undergo quiet then, as they asynchronously cross high threshold, cause degenerate quickly asynchronously. conclude that, any moment course HD, have an innocuous (but unstable) gene, process almost all neuron’s life.

Language: Английский

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Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 5587 - 5587

Published: May 21, 2024

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies ALS, particularly sporadic ALS of unknown diverse etiologies, we must identify key, convergent mechanisms disease pathogenesis. This review focuses on origin effects glutamate-mediated excitotoxicity in (the cortical hyperexcitability hypothesis), which increased glutamatergic signaling causes neurons to become hyperexcitable eventually die. We characterize both primary secondary contributions excitotoxicity, referring processes taking place at synapse within cell, respectively. ‘Primary pathways’ include upregulation calcium-permeable AMPA receptors, dysfunction EAAT2 astrocytic glutamate transporter, release from presynaptic terminal, reduced inhibition by interneurons—all have been observed patients model systems. ‘Secondary changes mitochondrial morphology function, production reactive oxygen species, endoplasmic reticulum (ER) stress. By identifying key targets cascade, emphasize importance pathway pathogenesis suggest that intervening could be developing disease.

Language: Английский

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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease

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

Published: Jan. 1, 2025

Language: Английский

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Pathogenesis of SCA3 and implications for other polyglutamine diseases

Neurobiology of Disease, Journal Year: 2019, Volume and Issue: 134, P. 104635 - 104635

Published: Oct. 24, 2019

Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG expansions in coding regions of respective disease genes. The nine polyQ Huntington's (HD), dentatorubral–pallidoluysian atrophy (DRPLA), spinal bulbar muscular (SBMA), and six spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, SCA17). underlying mechanism is thought principally to reflect dominant toxic properties proteins which, when harboring a expansion, differentially interact with protein partners are prone aggregate. Among SCA3 most common SCA, second HD prevalence worldwide. Here we summarize current understanding mechanisms within broader context field. We emphasize protein, ATXN3, new discoveries regarding three potential pathogenic mechanisms: 1) altered homeostasis; 2) DNA damage dysfunctional repair; 3) nonneuronal contributions disease. conclude an overview therapeutic implications recent mechanistic insights.

Language: Английский

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The contribution of glial cells to Huntington's disease pathogenesis

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 143, P. 104963 - 104963

Published: June 25, 2020

Glial cells play critical roles in the normal development and function of neural circuits, but many neurodegenerative diseases, they become dysregulated may contribute to brain pathology. In Huntington's disease (HD), glial both lose functions gain neuropathic phenotypes. addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression specific cell types is sufficient induce pathology disease-related impairments motor cognitive performance, suggesting that these drive certain aspects pathogenesis. support this imaging studies pre-symptomatic HD patients work on mouse models have suggested occurs at a very early stage disease, prior onset deficits. Furthermore, selectively ablating mHTT from or correcting for HD-induced changes their transcriptional profile rescues some HD-related phenotypes, demonstrating potential targeting therapeutic intervention. Here we review emerging research focused understanding involvement different This providing new insight into how impacts biological healthy as well induced might change way integrate circuits.

Language: Английский

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Molecular Pathophysiological Mechanisms in Huntington’s Disease

Biomedicines, Journal Year: 2022, Volume and Issue: 10(6), P. 1432 - 1432

Published: June 17, 2022

Huntington's disease is an inherited neurodegenerative described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be expanded CAG repeat on exon 1 of the huntingtin gene located chromosome 4. In following almost 30 years, a considerable amount research, using mainly animal models or vitro experiments, has tried unravel complex molecular cascades through which transcription mutant protein leads neuronal loss, especially medium spiny neurons striatum, and excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking reduced availability trophic factors crucial contributors. This review discusses pathogenic literature demise. However, due ubiquitous presence huntingtin, astrocytes are also dysfunctional, neuroinflammation may additionally contribute pathology. quest for therapies delay onset reduce rate progression ongoing, but based findings from basic research.

Language: Английский

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ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(5), P. 1359 - 1372

Published: Feb. 29, 2024

Language: Английский

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