Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Abstract Alzheimer’s disease (AD) brains are characterized by neuropathologic and biochemical changes that highly variable across individuals. Capturing epigenetic factors associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 measures (Braak stage, Thal phase, cerebral amyloid angiopathy score) brain levels five proteins (APOE, amyloid-β (Aβ)40, Aβ42, tau, p-tau) core to pathogenesis. Using a regional (rCpGm) approach, we identified 5,478 significant associations, 99.7% which were tau measures. Of the tau-associated rCpGms, 93 had concordant associations external datasets comprising 1,337 samples. Integrative transcriptome-methylome analyses uncovered 535 gene expression for these rCpGms. Genes concurrent perturbations enriched oligodendrocyte marker genes, including known risk genes such as BIN1 , myelination MYRF, MBP MAG previously implicated AD, well like LDB3 . further annotated top additional 6 single cell 2 bulk transcriptome from two other tauopathies, Pick’s progressive supranuclear palsy (PSP). Our findings support consistent rCpGm tauopathies tau-related phenotypes both tissue clusters. In summary, uncover integrative epigenomic landscape demonstrate common potential pathomechanism different tauopathies.

Язык: Английский

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CellFIE: Integrating Pathway Discovery With Pooled Profiling of Perturbations Uncovers Pathways of Huntington's Disease, Including Genetic Modifiers of Neuronal Development and Morphology

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Abstract Genomic screens and GWAS are powerful tools for identifying disease-modifying genes, but it is often challenging to understand the pathways by which these genes function. Here, we take an integrated approach that combines network analysis imaging-based pooled genetic perturbation study examine modifiers of Huntington’s disease (HD). The computational highlighted several in a subnetwork enriched neuronal development morphology. To test functional roles developed experimental pipeline allows CRISPRi KD 21 human iPSC-derived neurons followed optical genotypes, arborization, multiplexed pathway activity morphological fingerprint readout. This recovered known involved morphology confirmed unexpected links from between HD Our overcomes challenges measurement function health could be adapted other phenotypes neurological diseases.

Язык: Английский

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Montelukast improves disease outcome in SOD1^G93A female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity

British Journal of Pharmacology, Год журнала: 2024, Номер 181(18), С. 3303 - 3326

Опубликована: Май 15, 2024

Abstract Background and Purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss consequent muscle atrophy, for which no effective therapies are available. Recent findings reveal that disease progression fuelled early aberrant neuroinflammation the of oligodendrocytes with neuroprotective remyelinating properties. On this basis, pharmacological interventions capable restoring pro‐regenerative local milieu re‐establish proper oligodendrocyte functions may be beneficial. Experimental Approach Here, we evaluated in vivo therapeutic effects montelukast (MTK), an antagonist oligodendroglial G protein‐coupled receptor 17 (GPR17) cysteinyl‐leukotriene 1 (CysLT R) receptors on microglia astrocytes, SOD1 G93A ALS mouse model. We chronically treated mice MTK, starting from symptomatic stage. Disease was assessed behavioural immunohistochemical approaches. Key Results Oral MTK treatment significantly extended survival probability, delayed body weight ameliorated functionalityonly female mice. Noteworthy, restored maturation induced significant changes reactive phenotype morphological features microglia/macrophages astrocytes spinal cord mice, suggesting enhanced functions. Importantly, concomitant MN preservation has been detected after administration. No beneficial were observed male highlighting sex‐based difference protective activity MTK. Conclusions Implications Our results provide first preclinical evidence indicating repurposing safe marketed anti‐asthmatic drug, promising sex‐specific strategy personalized treatment.

Язык: Английский

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Single-nuclei transcriptome analysis of Huntington disease iPSC and mouse astrocytes implicates maturation and functional deficits

iScience, Год журнала: 2022, Номер 26(1), С. 105732 - 105732

Опубликована: Дек. 6, 2022

Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene that alters cellular homeostasis, particularly striatum and cortex. Astrocyte signaling establishes maintains neuronal functions are often altered under pathological conditions. We performed single-nuclei RNA-sequencing on human HD patient-induced pluripotent stem cell (iPSC)-derived astrocytes striatal cortical tissue from R6/2 mice to investigate high-resolution astrocyte state transitions. observed maturation glutamate mouse astrocytes. Human also showed upregulated actin-mediated signaling, suggesting some states may be cell-autonomous specific. In both species, astrogliogenesis transcription factors drive deficits, which supported rescued climbing deficits drosophila with NFIA knockdown. Thus, dysregulated induce dysfunctional astrocytic properties, part due influenced factor dysregulation.

Язык: Английский

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Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington’s disease mice and innervate the striatum

Molecular Therapy, Год журнала: 2023, Номер 31(12), С. 3545 - 3563

Опубликована: Окт. 7, 2023

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy transplanting human neural stem cells (hNSCs) is challenged by need for long-term functional integration. We previously described that, short-term hNSC transplantation into HD R6/2 mice, differentiated electrophysiologically active immature improving behavior biochemical deficits. Here, we show that (8 months) implantation hNSCs zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), electron microscopy demonstrate differentiate diverse neuronal populations, including MSN- interneuron-like cells, form connections. Single-nucleus RNA-seq analysis also shows restoration several mHTT-mediated transcriptional changes endogenous striatal mouse cells. Remarkably, engrafted receive synaptic inputs, innervate host improve membrane properties. Overall, findings support further evaluation clinical development HD.

Язык: Английский

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Omics and Network-based Approaches in Understanding HD Pathogenesis

IntechOpen eBooks, Год журнала: 2024, Номер unknown

Опубликована: Фев. 29, 2024

Huntington’s Disease (HD) is a rare, progressive neurodegenerative disease caused by CAG repeat expansion in the Huntingtin gene. HD an incurable disease; therefore, there growing need for effective therapeutic treatments and candidate biomarkers prognosis diagnosis of HD. Technological advancements over past couple years, have led to high-throughput experiments omics data. The use System Bioinformatics (SB) approaches, allows integration information across different -omics, this can clarify synergistic relationships biological molecules, resulting complex networks. SB network-based are able shed light on potential interactions genes, proteins, metabolites pathways participating pathogenesis how dysregulation these entities, affect age onset, severity progression. Moreover, −omics data analysis approaches provide better understanding molecules interact with each other provides drug targets that be used treat or delay symptom onset; opening door towards precision medicine. aim following chapter, discuss most popular -omics related research, popularity single cell analysis, repositories software available bulk analysis. In addition, regarding will also mentioned.

Язык: Английский

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Sex differences in Huntington's disease from a neuroinflammation perspective

Frontiers in Neurology, Год журнала: 2024, Номер 15

Опубликована: Июнь 10, 2024

Huntington's disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune dysregulation, prominently featuring increased immune activity, plays significant role in HD pathogenesis. In addition to the central nervous system (CNS), systemic innate activation inflammation are observed patients, exacerbating effects of Huntingtin (HTT) gene mutation. Recent attention sex differences symptom severity underscores need consider gender as biological variable research. Understanding sex-specific responses holds promise for elucidating pathophysiology informing targeted treatment strategies mitigate functional decline. This perspective will highlight importance investigating influence HD, particularly focusing on predisposing individuals disease.

Язык: Английский

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Mapping the glial transcriptome in Huntington’s disease using snRNAseq: selective disruption of glial signatures across brain regions

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Окт. 21, 2024

Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative with a fatal outcome. There accumulating evidence of prominent role glia in the pathology HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) human post mortem brain four differentially affected regions; caudate nucleus, frontal cortex, hippocampus cerebellum. Across 127,205 nuclei from donors HD age/sex matched controls, found heterogeneity which altered HD. We describe changes abundance certain subtypes astrocytes, microglia, oligodendrocyte precursor cells oligodendrocytes between control samples, these differences are widespread across regions. Furthermore, highlight possible mechanisms that characterise glial contribution to including depletion myelinating oligodendrocytes, oligodendrocyte-specific upregulation calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1 A ( PDE1A ) molecular chaperones as cross-glial signature potential adaptive response accumulation mutant huntingtin (mHTT). Our results support hypothesis have important show all types disease.

Язык: Английский

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Neuroinflammatory Proteins in Huntington’s Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(21), С. 11787 - 11787

Опубликована: Ноя. 2, 2024

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by CAG tract expansion in the huntingtin gene (

Язык: Английский

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Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model

Neurobiology of Disease, Год журнала: 2023, Номер 187, С. 106313 - 106313

Опубликована: Сен. 28, 2023

Expansion of a triplet repeat tract in exon 1 the HTT gene causes Huntington's disease (HD). The mutant protein (mHTT) has numerous aberrant interactions with diverse, pleiomorphic effects. Lowering mHTT is promising approach to treat HD, but it unclear when lowering should be initiated, how much necessary, and what duration occur achieve benefits. Furthermore, effects on brain lipids have not been assessed. Using mHtt-inducible mouse model, we analyzed mHtt initiated at different ages sustained for time-periods. cytoplasmic synaptic compartments striatum was reduced 38-52%; however, there minimal nuclear perinuclear regions where aggregates formed 12 months age. Total striatal were 9-month-old LacQ140 mice preserved by lowering. Subclasses important white matter structure function including ceramide (Cer), sphingomyelin (SM), monogalactosyldiacylglycerol (MGDG), contributed reduction total lipids. Phosphatidylinositol (PI), phosphatidylserine (PS), bismethyl phosphatidic acid (BisMePA) also changed mice. Levels all subclasses except mRNA expression profiling indicated that transcriptional mechanism contributes changes myelin lipids, some can prevented Our findings suggest early prevent levels select proteins most misfolded, degradation-resistant form hampers benefits long term.

Язык: Английский

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