Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 353 - 396
Опубликована: Янв. 1, 2024
Язык: Английский
Nature Neuroscience, Год журнала: 2025, Номер unknown
Опубликована: Янв. 6, 2025
Язык: Английский
Процитировано
2
Cell, Год журнала: 2025, Номер unknown
Опубликована: Фев. 1, 2025
Highlights•Mismatch-repair genes drive striatal and cortical neuronal pathogenesis in HD mice•Linear rate of CAG expansion neurons is dependent on Msh3 Pms1•Somatic elicits repeat-length -threshold-dependent pathologies•Msh3 deficiency corrects synaptic, astrocytic, locomotor defects miceSummaryHuntington's disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to remain unclear. Here, we genetically tested 9 genome-wide association study (GWAS)/MMR mutant Huntingtin (mHtt) mice with 140 inherited repeats (Q140). Knockout (KO) encoding a distinct MMR complex either strongly (Msh3 Pms1) or moderately (Msh2 Mlh1) rescues phenotypes early onset medium-spiny (MSNs) late the neurons: somatic CAG-repeat expansion, transcriptionopathy, mHtt aggregation. ameliorates open-chromatin dysregulation Q140 neurons. Mechanistically, fast linear modal-CAG-repeat MSNs (8.8 repeats/month) drastically reduced stopped by mutants. Pms1 prevents aggregation keeping MSN length below 150. Importantly, mice. Thus, CAG-expansion rates HD-vulnerable elicit repeat-length/threshold-dependent, selective, progressive vivo.Graphical abstract
Язык: Английский
Процитировано
1
Trends in Molecular Medicine, Год журнала: 2023, Номер 29(10), С. 802 - 816
Опубликована: Авг. 15, 2023
Язык: Английский
Процитировано
16
Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17
Опубликована: Май 3, 2023
In this review, we first describe the current understanding of glial-mediated vascular function affecting role blood-brain barrier (BBB) in central nervous system (CNS) disorders. BBB, mainly composed glial and endothelial cells (ECs), is protective structure that orchestrates transport substances, including ions, molecules, from brain vessels into or out CNS. Then, display multiple communication between based on angiogenesis, wrapping, blood perfusion brain. Glial can support microvascular ECs to form a network connecting neurons. Astrocytes, microglia, oligodendrocytes are common types surrounding vessel. Glial-vessel interaction required for permeability integrity BBB. cerebral transmit signals regulate activity growth factor (VEGF) Wnt-dependent angiogenesis mechanism. addition, these monitor flow via Ca
Язык: Английский
Процитировано
14
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown
Опубликована: Ноя. 2, 2023
Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the first exon of HTT gene encoding huntingtin. Prior reports have established correlation between expanded and altered expression. However, mechanisms leading to disruption RNA processing HD remain unclear. Here, our analysis reported protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing targeted RASL-seq RNAs from cortex striatum mouse model R6/2 reveals increased skipping which confirmed Q150 Q175 knock-in mice human brain. We identify RBP TDP-43 N6-methyladenosine (m6A) writer methyltransferase 3 (METTL3) be upstream regulators HD. Along this novel mechanistic insight, we observe decreased nuclear localization cytoplasmic accumulation phosphorylated In addition, co-localizes brain forming aggregate-like bodies distinct mutant inclusions or previously observed pathologies. Binding onto HD-associated differentially expressed aberrantly spliced genes decreased. Finally, m6A modification reduced on abnormally brain, including at clustered sites adjacent binding sites. Our evidence supports loss function coupled as mechanism underlying alternative splicing/unannotated usage highlights critical nature across multiple diseases.
Язык: Английский
Процитировано
13
Molecular Diagnosis & Therapy, Год журнала: 2023, Номер 27(5), С. 553 - 561
Опубликована: Авг. 8, 2023
Neurodegenerative disorders are typically characterized by late onset progressive damage to specific (sub)populations of cells the nervous system that essential for mobility, coordination, strength, sensation, and cognition. Addressing this selective cellular vulnerability has become feasible with emergence single-cell-omics technologies, which now represent state-of-the-art approach profile heterogeneity complex tissues including human post-mortem brain at unprecedented resolution. In review, we briefly recapitulate experimental workflow single-cell RNA sequencing summarize recent knowledge acquired it in most common neurodegenerative diseases: Parkinson's, Alzheimer's, Huntington's disease, multiple sclerosis. We also discuss possibility applying approaches diagnostics therapy disorders, as well limitations. While currently point deeply exploring transcriptomic changes affected cells, further technological developments hold a promise manipulating pathways once understand them better.
Язык: Английский
Процитировано
12
Heliyon, Год журнала: 2024, Номер 10(7), С. e28119 - e28119
Опубликована: Апрель 1, 2024
The association between dietary vitamin B1 intake and cognitive performance in the noninstitutionalized older adult population of United States remains unclear.
Язык: Английский
Процитировано
4
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Авг. 8, 2024
The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington's disease (HD) have not been fully defined. To explore role of astrocytes this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, multiplexed immunofluorescence on HD control post-mortem brains. We identified genes that correlated with repeat length, which were enriched astrocyte genes, lipidomic signatures implicated poly-unsaturated fatty acids sensitizing neurons cell death. Because play essential roles lipid metabolism, explored heterogeneity astrocytic states both protoplasmic fibrous-like (CD44+) astrocytes. Significantly, one state showed high levels metallothioneins was distinct striatal neuronal populations. When modeled vitro, improved viability HD-patient-derived spiny projection neurons. Our findings uncover key protecting against HD. is a neurodegenerative shows vulnerability. Here, authors show postmortem brain are regionally diverse, disease-associated cortical compensatory mitigated neural
Язык: Английский
Процитировано
4
Neurobiology of Disease, Год журнала: 2024, Номер unknown, С. 106672 - 106672
Опубликована: Сен. 1, 2024
Язык: Английский
Процитировано
4
Neurology International, Год журнала: 2025, Номер 17(1), С. 6 - 6
Опубликована: Янв. 13, 2025
Neuroinflammation is a blanket term that describes the body’s complex inflammatory response in central nervous system (CNS). It encompasses phenotype shift to proinflammatory state, release of cytokines, recruitment peripheral immune cells, and wide variety other processes. has been implicated nearly every major CNS disease ranging from Alzheimer’s brain cancer. Understanding modeling neuroinflammation critical for identification novel therapeutic targets treatment diseases. Unfortunately, translation findings non-human models left much be desired. This review systematically discusses role human pluripotent stem cell (hPSC)-derived glia supporting cells within CNS, including astrocytes, microglia, oligodendrocyte precursor pericytes, endothelial describe state field hope future discoveries. hPSC-derived offer an expanded potential study pathobiology immunomodulatory cascades impact progression. While progress made development models, there explore application these understand CNS.
Язык: Английский
Процитировано
0