scholarly journals Single-cell atlas of progressive supranuclear palsy reveals a distinct hybrid glial cell population

2021 ◽  
Author(s):  
Abhijeet Sharma ◽  
Won-Min Song ◽  
Kurt Farrell ◽  
Kristen Whitney ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Single Cell ◽  
Neurodegenerative Disorder ◽  
Hybrid Cell ◽  
Unfolded Protein ◽  
Homeostatic Function ◽  
Single Nucleus ◽  
Cell Type Specific ◽  
The Unfolded Protein Response ◽  
Protein Response

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder whose molecular complexity at a single cell level has not been evaluated. Here we analyzed 45,559 high quality nuclei from the subthalamic nucleus and associated basal ganglia regions from post-mortem human PSP brains with varying degrees of tau pathology compared to controls (n=3 per group). We identified novel astrocyte-oligodendrocyte hybrid cell populations that overexpress neurotropic factors in conjunction with suppression of the unfolded protein response pathway. Notably, trajectory analysis identified subpopulations of hybrid cells with distinct astrocytic, oligodendrocytic and hybrid molecular states that change from a neuroprotective hybrid cell to an astrocytic cell with impaired homeostatic function in PSP. Our single nucleus transcriptomic data provides insights into the cell-type-specific contributions to the disease for investigating the molecular and cellular basis of PSP

scholarly journals Single cell RNAseq uncovers a robust transcriptional response to morphine by oligodendrocytes

2018 ◽  
Author(s):  
Denis Avey ◽  
Sumithra Sankararaman ◽  
Aldrin K. Y. Yim ◽  
Ruteja Barve ◽  
Robi D. Mitra ◽  
...  
Keyword(s):  
Single Cell ◽  
Differential Expression Analysis ◽  
Transcriptional Response ◽  
Cell Types ◽  
Unfolded Protein ◽  
Cell Type Specific ◽  
Cellular Pathways ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Shed Light

SUMMARYMolecular and behavioral responses to opioids are thought to be primarily mediated by neurons, although there is accumulating evidence that other cell types also play a role in drug addiction. To investigate cell-type-specific opioid responses, we performed single-cell RNA sequencing of the nucleus accumbens of mice following acute morphine treatment. Differential expression analysis uncovered robust morphine-dependent changes in gene expression in oligodendrocytes. We examined the expression of selected genes, including Cdkn1a and Sgk1, by FISH, confirming their induction by morphine in oligodendrocytes. Further analysis using RNAseq of FACS-purified oligodendrocytes revealed a large cohort of morphine-regulated genes. Importantly, the affected genes are enriched for roles in cellular pathways intimately linked to oligodendrocyte maturation and myelination, including the unfolded protein response. Altogether, our data shed light on a novel, morphine-dependent transcriptional response by oligodendrocytes that may contribute to the myelination defects observed in human opioid addicts.

scholarly journals The Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy

Circulation ◽  
2021 ◽  
Author(s):  
Dries A.M. Feyen ◽  
Isaac Perea-Gil ◽  
Renee G.C. Maas ◽  
Magdalena Harakalova ◽  
Alexandra A. Gavidia ◽  
...  
Keyword(s):  
Single Cell ◽  
Unfolded Protein Response ◽  
Rna Sequencing ◽  
Therapeutic Potential ◽  
Compensatory Mechanism ◽  
Unfolded Protein ◽  
Single Cell Rna Sequencing ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact

Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy (DCM) with a high prevalence of ventricular arrhythmias. How the R14 deletion causes DCM is poorly understood and there are no disease-specific therapies. Methods: We used single-cell RNA sequencing to uncover PLN R14del disease-mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We utilized both 2D and 3D functional contractility assays to evaluate the impact of modulating disease relevant pathways in PLN R14del hiPSC-CMs. Results: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro . Single-cell RNA sequencing revealed the induction of the unfolded protein response pathway (UPR) in PLN R14del compared to isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the three main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP protein Inducer X (BiX). PLN R14del hiPSC-CMs treated with BiX showed a dose-dependent amelioration of the contractility deficit of in both 2D cultures and 3D engineered heart tissues without affecting calcium homeostasis. Conclusions: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.

scholarly journals Activation of the Unfolded Protein Response and Proteostasis Disturbance in Parkinsonism-Dementia of Guam

2019 ◽  
Author(s):  
Bert M Verheijen ◽  
Celina Lussier ◽  
Cora Müller-Hübers ◽  
Ralph M Garruto ◽  
Kiyomitsu Oyanagi ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Ubiquitin Proteasome System ◽  
Mariana Islands ◽  
Unfolded Protein ◽  
Intracellular Protein Degradation ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Guam parkinsonism-dementia (G-PD) is a progressive and fatal neurodegenerative disorder among the native inhabitants of the Mariana Islands that manifests clinically with parkinsonism as well as dementia. Neuropathologically, G-PD is characterized by abundant neurofibrillary tangles composed of hyperphosphorylated tau, marked deposition of transactive response DNA-binding protein 43 kDa (TDP-43), and neuronal loss. The mechanisms that underlie neurodegeneration in G-PD are poorly understood. Here, we report that the unfolded protein response (UPR) is activated in G-PD brains. Specifically, we show that the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa and phosphorylated (activated) ER stress sensor protein kinase RNA-like ER kinase accumulate in G-PD brains. Furthermore, proteinaceous aggregates in G-PD brains are found to contain several proteins related to the ubiquitin-proteasome system (UPS) and the autophagy pathway, two major mechanisms for intracellular protein degradation. In particular, a mutant ubiquitin (UBB+1), whose presence is a marker for UPS dysfunction, is shown to accumulate in G-PD brains. We demonstrate that UBB+1 is a potent modifier of TDP-43 aggregation and cytotoxicity in vitro. Overall, these data suggest that UPR activation and intracellular proteolytic pathways are intimately connected with the accumulation of aggregated proteins in G-PD.

scholarly journals A Multiplexed Single-Cell CRISPR Screening Platform Enables Systematic Dissection of the Unfolded Protein Response

Cell ◽  
2016 ◽  
Vol 167 (7) ◽  
pp. 1867-1882.e21 ◽  
Author(s):  
Britt Adamson ◽  
Thomas M. Norman ◽  
Marco Jost ◽  
Min Y. Cho ◽  
James K. Nuñez ◽  
...  
Keyword(s):  
Single Cell ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Screening Platform ◽  
The Unfolded Protein Response ◽  
Protein Response
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