Toxicology Letters, Год журнала: 2025, Номер 406, С. 20 - 30
Опубликована: Фев. 14, 2025
Язык: Английский
Nature Reviews Drug Discovery, Год журнала: 2023, Номер 23(1), С. 23 - 42
Опубликована: Ноя. 27, 2023
Язык: Английский
Процитировано
44
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
26
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3845 - 3845
Опубликована: Март 29, 2024
Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in huntingtin gene (HTT), resulting production mutant protein (mHTT) with a polyglutamine stretch its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates accumulates abnormally neuronal nuclei processes, leading to disruptions multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made developing various therapeutic strategies treat HD. In addition drugs targeting toxicity mHTT, therapy approaches that aim reduce expression HTT hold great promise therapy. This review provides an overview current treatments, discusses different strategies, aims facilitate future advancements field.
Язык: Английский
Процитировано
20
Nature reviews. Immunology, Год журнала: 2024, Номер unknown
Опубликована: Дек. 9, 2024
Язык: Английский
Процитировано
16
Cell, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
12
Current Opinion in Neurobiology, Год журнала: 2024, Номер 86, С. 102877 - 102877
Опубликована: Апрель 16, 2024
Язык: Английский
Процитировано
12
Brain Behavior and Immunity, Год журнала: 2024, Номер 119, С. 317 - 332
Опубликована: Март 27, 2024
Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate activity in vitro, expressed the brain, associated with increased schizophrenia risk. Beyond this, little known about CSMD1 including whether it regulates brain or otherwise plays a role neurodevelopment. We used biochemical, immunohistochemical, proteomic techniques to examine regional, cellular, subcellular distribution as protein interactions of brain. To evaluate involved complement-mediated synapse elimination, we examined Csmd1-knockout mice CSMD1-knockout human stem cell-derived neurons. interrogated circuit development mouse visual thalamus, process that involves pathway activity. also quantified deposition on synapses thalamus cultured Finally, assessed uptake synaptosomes by microglia. found present at interacts Mice lacking Csmd1 displayed levels component C3, an colocalization C3 presynaptic terminals, fewer retinogeniculate synapses, aberrant segregation eye-specific retinal inputs critical period complement-dependent refinement this circuit. Loss vivo enhanced synaptosome engulfment microglia effect was dependent microglial receptor, CR3. neurons were more vulnerable deposition. These data suggest function regulator CNS development.
Язык: Английский
Процитировано
9
Current Neurology and Neuroscience Reports, Год журнала: 2024, Номер 24(8), С. 255 - 264
Опубликована: Июнь 11, 2024
Язык: Английский
Процитировано
9
Journal of Neurorestoratology, Год журнала: 2024, Номер 12(3), С. 100136 - 100136
Опубликована: Июнь 13, 2024
Remarkable advancements have been made in understanding the pathogenesis of Alzheimer's disease, Parkinson's and other neurological disease; our depth neurorestorative mechanisms such as anti-inflammatory processes, immune regulation, neuromodulation, neovascularization/neural repair, neuroprotection; clinical treatments. Multiple types cell therapies reported, with some positive outcomes. Diverse forms neurostimulation neuromodulation well brain–computer interfaces shown good therapeutic outcomes applications. Further, surgery pharmaceutic therapy very impressive. These fundamental achievements are helpful for diseases neurorestoration. Patients impairments benefited from progress, but these still require confirmation higher-level randomized trials.
Язык: Английский
Процитировано
9
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Июнь 29, 2024
Abstract Microglia are important players in surveillance and repair of the brain. Implanting an electrode into cortex activates microglia, produces inflammatory cascade, triggers foreign body response, opens blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging implanted microelectrodes, we test hypothesis that low-intensity pulsed ultrasound stimulation reduce microglia-mediated neuroinflammation following implantation microelectrodes. In first week treatment, found increased microglia migration speed by 128%, enhanced expansion area 109%, a reduction microglial activation 17%, indicating improved tissue healing surveillance. Microglial coverage microelectrode was reduced 50% astrocytic scarring 36% resulting increase recording performance at chronic time. The data indicate helps response around
Язык: Английский
Процитировано
9