NG2 glia protect against prion neurotoxicity by inhibiting prostaglandin E2 signaling DOI Creative Commons
Yingjun Liu, Jingjing Guo,

Maja Matoga

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 4, 2023

Abstract Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. This raises the question of how myelinating cells interact with processes. Here, we found that glia were activated after prion infection cerebellar organotypic cultured slices (COCS) and brains prion-inoculated mice. In both model systems, depletion exacerbated prion-induced neurodegeneration accelerated pathology. Loss unleashed a microglial reaction promoting biosynthesis prostaglandin E2 (PGE2), which augmented neurotoxicity HovS cell line, primary neurons COCS through binding to EP4 receptor. Single-cell RNA sequencing revealed molecular signatures inflammatory, disease-associated MHC + microglia but not interferon-responsiveness PGE2-producing Pharmacological or genetic inhibition PGE2 attenuated mice, reduced enhanced NG2-glia-depleted infection, dampened acceleration disease These data unveil non-cell-autonomous interaction between suggest signaling may represent an actionable target against diseases.

Язык: Английский

A single-cell map of antisense oligonucleotide activity in the brain DOI Creative Commons
Meredith A Mortberg, Juliana E Gentile, Naeem Nadaf

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 51(14), С. 7109 - 7124

Опубликована: Май 16, 2023

Abstract Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the central nervous system (CNS). By modulating RNA, they hold promise of targeting root molecular causes disease and potential to treat myriad CNS disorders. Realization this requires that ASOs must be active in disease-relevant cells, ideally, monitorable biomarkers also reflect ASO activity these cells. The biodistribution such centrally delivered have been deeply characterized rodent non-human primate (NHP) models, but usually only bulk tissue, limiting our understanding distribution across individual cells diverse cell types. Moreover, human clinical trials, target engagement is a single compartment, CSF. We sought deeper how types contribute tissue signal CNS, are linked CSF biomarker outcomes. employed nucleus transcriptomics on from mice treated with RNase H1 against Prnp Malat1 NHPs an PRNP. Pharmacologic was observed every type, though sometimes substantial differences magnitude. Single RNA count distributions implied suppression sequenced cell, rather than intense knockdown some Duration action up 12 weeks post-dose differed types, being shorter microglia neurons. Suppression neurons generally similar to, or more robust than, tissue. In macaques, PrP lowered 40% conjunction PRNP all including neurons, arguing readout likely pharmacodynamic effect neuronal disorder. Our results provide reference dataset for establish sequencing as method evaluating type specificity oligonucleotide therapeutics other modalities.

Язык: Английский

Процитировано

28
NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling DOI Creative Commons
Yingjun Liu, Jingjing Guo, Maja Matoga

и другие.

Nature Neuroscience, Год журнала: 2024, Номер 27(8), С. 1534 - 1544

Опубликована: Май 27, 2024

Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. Here, we identify a neuroprotective role for glia against prion toxicity. were activated after infection cerebellar organotypic cultured slices (COCS) and brains of prion-inoculated mice. In both model systems, depletion exacerbated prion-induced neurodegeneration accelerated pathology. Loss enhanced the biosynthesis prostaglandin E2 (PGE2) by microglia, which augmented neurotoxicity through binding to EP4 receptor. Pharmacological or genetic inhibition PGE2 attenuated COCS mice, reduced NG2-glia-depleted infection, dampened acceleration disease These data unveil non-cell-autonomous interaction between microglia suggest that signaling may represent an actionable target diseases.

Язык: Английский

Процитировано

8
Region-Specific Homeostatic Identity of Astrocytes Is Essential for Defining Their Response to Pathological Insults DOI Creative Commons

Natallia Makarava,

Olga Mychko,

Kara Molesworth

и другие.

Cells, Год журнала: 2023, Номер 12(17), С. 2172 - 2172

Опубликована: Авг. 30, 2023

The transformation of astrocytes into reactive states constitutes a biological response the central nervous system under variety pathological insults. Astrocytes display diverse homeostatic identities that are developmentally predetermined and regionally specified. Upon associated with neurodegenerative diseases other neurological disorders, acquire phenotypes. However, it is not clear whether their phenotypes dictated by region-specific identity or nature an insult. To address this question, gene expression profiling was performed for four brain regions (cortex, hippocampus, thalamus, hypothalamus) in mice using custom NanoString panel consisting selected sets genes astrocyte functions reactivity five conditions: prion disease, traumatic injury, ischemia, 5XFAD Alzheimer’s disease model normal aging. states, predominantly were found to respond insults manner. Regardless insult insult-specificity response, strong correlations between undirected GSA (gene set analysis) scores reporting on observed within each individual region. insult-specific signatures did separate well from instead partially overlapped, forming continuums. current study demonstrates important defining Within populations, show continuums signatures, overlapping

Язык: Английский

Процитировано

11
Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies DOI Creative Commons
Walker S. Jackson, Susanne Bauer, Lech Kaczmarczyk

и другие.

Biology, Год журнала: 2024, Номер 13(2), С. 67 - 67

Опубликована: Янв. 23, 2024

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across regions, mixture cell types therein obscures experimental results. In recent years, methods that analyze transcriptomes individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and provided invaluable specific types. Concurrently, transgene-based techniques dissect type-specific translatomes (CSTs) in model systems, like RiboTag bacTRAP, unique advantages but received less attention. This review juxtaposes merits drawbacks both methodologies, focusing use CSTs understanding conditions amyotrophic lateral sclerosis (ALS), Huntington’s (HD), Alzheimer’s (AD), prion fatal familial insomnia (FFI), genetic Creutzfeldt–Jakob (gCJD), acquired disease. We conclude by discussing emerging trends observed multiple methods.

Язык: Английский

Процитировано

3
The Role of Glial Cells in Neurobiology and Prion Neuropathology DOI Creative Commons
Arielle Hay, Katriana A. Popichak, Julie A. Moreno

и другие.

Cells, Год журнала: 2024, Номер 13(10), С. 832 - 832

Опубликована: Май 14, 2024

Prion diseases are rare and neurodegenerative that characterized by the misfolding infectious spread of prion protein in brain, causing progressive irreversible neuronal loss associated clinical behavioral manifestations humans animals, ultimately leading to death. The brain has a complex network neurons glial cells whose crosstalk is critical for function homeostasis. Although it established infection necessary disease occur, debate remains field as role played cells, namely astrocytes microglia, whether these beneficial host or further accelerate disease. Here, we review current literature assessing morphologies between two cell types, prion-infected brain.

Язык: Английский

Процитировано

2
Multiomic Analyses Direct Hypotheses for Creutzfeldt-Jakob Disease Risk Genes DOI
Fahri Küçükali, Elizabeth Hill, Tijs Watzeels

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 21, 2024

Abstract Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation itself, molecular risk factors not well understood. Prion prion-like mechanisms thought to underpin disorders meaning elucidation could have broad relevance. Herein we sought further develop our understanding confer sCJD using a systematic gene prioritization functional interpretation pipeline based on multiomic integrative analyses. We integrated published genome-wide association study (GWAS) summary statistics publicly available bulk brain cell type expression datasets. performed multiple transcriptome proteome-wide studies (TWAS & PWAS) Bayesian genetic colocalization analyses between signals quantitative trait loci signals. then applied obtained results nominated prioritized genes risk-associated manner. Genetic upregulation both syntaxin-6 ( STX6 ) was associated datasets, regulation specific oligodendrocytes. Similarly, increased disulfide isomerase family A member 4 PDIA4 ), involved unfolded response, linked risk, particularly excitatory neurons. Protein mesencephalic astrocyte derived neurotrophic factor MANF protection against endoplasmic reticulum stress sulfatide binding (linking enzyme final step synthesis, encoded by GAL3ST1 identified as protective sCJD. In total 32 were into two tiers level evidence confidence for studies. This provides insights genetically-associated underlying susceptibility prioritizes hypotheses exploration beyond itself previously highlighted through newly mechanisms. These findings highlight importance glial cells, sulfatides neuron response pathogenesis.

Язык: Английский

Процитировано

0
Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease DOI Creative Commons
Jessy A. Slota,

Lise Lamoureux,

Kathy L. Frost

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 23, 2024

Язык: Английский

Процитировано

0
Excitatory neuron-prone prion propagation and excitatory neuronal loss in prion-infected mice DOI Creative Commons

Temuulen Erdenebat,

Yusuke Komatsu,

Nozomi Uwamori

и другие.

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Дек. 12, 2024

The accumulation of a disease-specific isoform prion protein (PrP Sc ) and histopathological lesions, such as neuronal loss, are unevenly distributed in the brains humans animals affected with diseases. This distribution varies depending on diseases and/or combinations strain experimental animal. brain region-dependent PrP neuropathological lesions suggests cell-type-dependent propagation vulnerability to infection. However, underlying mechanism is largely unknown. In this study, we provided evidence that 22L propagates more efficiently excitatory neurons than inhibitory thalamus vulnerable was less intense striatum, where GABAergic predominate, compared cerebral cortex thalamus, glutamatergic predominant, mice intracerebrally or intraperitoneally inoculated strain. stains were observed along needle track after stereotaxic injection into whereas they also away from thalamus. Consistent inefficient propagated primary cultures. RNAscope situ hybridization revealed decrease Vglut1 - Vglut2 -expressing ventral posterolateral nuclei strain-infected mice, no Vgat adjacent reticular nucleus, mainly composed interneurons. neuron-prone loss shed light

Язык: Английский

Процитировано

0
A single-cell map of antisense oligonucleotide activity in the brain DOI Creative Commons
Meredith A Mortberg, Juliana E Gentile, Naeem Nadaf

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Фев. 14, 2023

Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the brain and hold promise of treating myriad diseases by modulating RNA. CNS tissue is not routinely biopsied in living individuals, leading to reliance on CSF biomarkers inform drug target engagement. Animal models can link parenchyma, but our understanding how individual cells contribute bulk signal limited. Here we employed single nucleus transcriptomics from mice treated with RNase H1 ASOs against Prnp Malat1 macaques an ASO PRNP . Activity was observed every cell type, though sometimes substantial differences magnitude. Single RNA count distributions implied suppression sequenced cell, rather than intense knockdown only some cells. Duration action up 12 weeks post-dose differed across types, being shorter microglia neurons. Suppression neurons generally similar to, or more robust than, tissue. In macaques, PrP lowered 40% conjunction all types including neurons, arguing that a biomarker readout likely reflect disease-relevant neuronal disorder.

Язык: Английский

Процитировано

1
NG2 glia protect against prion neurotoxicity by inhibiting prostaglandin E2 signaling DOI Creative Commons
Yingjun Liu, Jingjing Guo,

Maja Matoga

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 4, 2023

Abstract Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. This raises the question of how myelinating cells interact with processes. Here, we found that glia were activated after prion infection cerebellar organotypic cultured slices (COCS) and brains prion-inoculated mice. In both model systems, depletion exacerbated prion-induced neurodegeneration accelerated pathology. Loss unleashed a microglial reaction promoting biosynthesis prostaglandin E2 (PGE2), which augmented neurotoxicity HovS cell line, primary neurons COCS through binding to EP4 receptor. Single-cell RNA sequencing revealed molecular signatures inflammatory, disease-associated MHC + microglia but not interferon-responsiveness PGE2-producing Pharmacological or genetic inhibition PGE2 attenuated mice, reduced enhanced NG2-glia-depleted infection, dampened acceleration disease These data unveil non-cell-autonomous interaction between suggest signaling may represent an actionable target against diseases.

Язык: Английский

Процитировано

1