Archives of Pharmacal Research, Год журнала: 2020, Номер 43(9), С. 920 - 931
Опубликована: Сен. 1, 2020
Язык: Английский
Molecular Metabolism, Год журнала: 2022, Номер 61, С. 101502 - 101502
Опубликована: Апрель 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
Язык: Английский
Процитировано
84
Nature Medicine, Год журнала: 2023, Номер 29(11), С. 2866 - 2884
Опубликована: Окт. 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.
Язык: Английский
Процитировано
72
Archives of Toxicology, Год журнала: 2024, Номер 98(3), С. 579 - 615
Опубликована: Янв. 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
Язык: Английский
Процитировано
29
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Май 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.
Язык: Английский
Процитировано
27
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5587 - 5587
Опубликована: Май 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.
Язык: Английский
Процитировано
20
Cell, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
19
Neurobiology of Disease, Год журнала: 2019, Номер 134, С. 104635 - 104635
Опубликована: Окт. 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.
Язык: Английский
Процитировано
140
Neurobiology of Disease, Год журнала: 2020, Номер 143, С. 104963 - 104963
Опубликована: Июнь 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.
Язык: Английский
Процитировано
81
Biomedicines, Год журнала: 2022, Номер 10(6), С. 1432 - 1432
Опубликована: Июнь 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.
Язык: Английский
Процитировано
64
Nucleic Acids Research, Год журнала: 2019, Номер unknown
Опубликована: Окт. 16, 2019
Abstract Huntington disease (HD) is a fatal neurodegenerative caused by pathogenic expansion of CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine tolerability efficacy non-selective lowering with an AAV5 encoded miRNA (AAV5-miHTT) humanized Hu128/21 mouse model We show that intrastriatal administration AAV5-miHTT results potent sustained suppression at least 7 months post-injection. Importantly, was generally tolerated, however high dose did induce astrogliosis. observed improvement select behavioural modest neuropathological HD-like phenotypes mice, suggesting potential therapeutic benefit miRNA-mediated lowering. Finally, also reduction wild type (wtHTT) Hu21 control mice tolerated up to post-injection but may impairment motor coordination striatal atrophy. Taken together, our data suggests context HD, benefits mHTT outweigh potentially detrimental effects wtHTT loss following
Язык: Английский
Процитировано
66