scholarly journals Single-Cell RNA Sequencing in Parkinson’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 368
Author(s):  
Shi-Xun Ma ◽  
Su Bin Lim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Rna Degradation ◽  
Postmortem Brain ◽  
Cell Type ◽  
New Findings ◽  
Postmortem Brain Tissue ◽  
Technical Challenges

Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have enhanced the understanding of the molecular pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Nonetheless, their application in PD has been limited due mainly to the technical challenges resulting from the scarcity of postmortem brain tissue and low quality associated with RNA degradation. Despite such challenges, recent advances in animals and human in vitro models that recapitulate features of PD along with sequencing assays have fueled studies aiming to obtain an unbiased and global view of cellular composition and phenotype of PD at the single-cell resolution. Here, we reviewed recent sc/snRNA-seq efforts that have successfully characterized diverse cell-type populations and identified cell type-specific disease associations in PD. We also examined how these studies have employed computational and analytical tools to analyze and interpret the rich information derived from sc/snRNA-seq. Finally, we highlighted important limitations and emerging technologies for addressing key technical challenges currently limiting the integration of new findings into clinical practice.

scholarly journals Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson's Disease and Multiple System Atrophy

2021 ◽  
Author(s):  
Rahul Pande ◽  
Yinyin Huang ◽  
Erin Teeple ◽  
Pooja Joshi ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Single Cell ◽  
Alpha Synuclein ◽  
Cell Type ◽  
Distinct Cell Type ◽  
Altered Expression ◽  
Cell Type Specific ◽  
Disease Specific

Understanding disease biology at a cellular level from disease specific tissues is imperative for effective drug development for complex neurodegenerative diseases. We profiled 87,086 nuclei from putamen tissue of healthy controls, Parkinson's Disease (PD), and Multiple System Atrophy (MSA) subjects to construct a comprehensive single cell atlas. Although both PD and MSA are manifestations of alpha-synuclein protein aggregation, we observed that both the diseases have distinct cell-type specific changes. We see a possible expansion and activation of microglia and astrocytes in PD compared to MSA and controls. Contrary to PD microglia, we found absence of upregulated unfolded protein response in MSA microglia compared to controls. Differentially expressed genes in major cell types are enriched for genes associated with PD-GWAS loci. We found altered expression of major neurodegeneration associated genes, SNCA, MAPT, LRRK2, and APP, at cell-type resolution. We also identified disease associated gene modules using a network biology approach. Overall, this study creates an interactive atlas from synucleinopathies and provides major cell-type specific disease insights.

scholarly journals CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Yuanyuan Li ◽  
Mengyue Niu ◽  
Aonan Zhao ◽  
Wenyan Kang ◽  
Zhichun Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cxcr4 Expression ◽  
Postmortem Brain ◽  
Primary Microglia ◽  
Postmortem Brain Tissue ◽  
Culture Models ◽  
Novel Target ◽  
The Relationship ◽  
Cell Culture Models

Abstract Background The mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity. Migration of microglia to the substantia nigra (SN) could precede neurodegeneration in A53T mice. We hypothesized that CXCL12 could be a mediator in the α-synuclein-induced migration of microglia. Methods After establishing appropriate animal and cell culture models, we explored the relationship between α-synuclein and CXCL12 in A53T mice, primary microglia, and BV-2 cell lines. We also explored the mechanisms of these interactions and the signaling processes involved in neuroinflammation. Results We confirmed the positive correlation between α-synuclein and CXCL12 in the postmortem brain tissue of PD patients and the upregulated CXCR4 expression in SN microglia of A53T mice. In addition, as expected, α-synuclein increased the production of CXCL12 in microglia via TLR4/IκB-α/NF-κB signaling. Importantly, CXCL12/CXCR4/FAK/Src/Rac1 signaling was shown to be involved in α-synuclein-induced microglial accumulation. Conclusions Our study suggests that CXCL12 could be a novel target for the prevention of α-synuclein-triggered ongoing microglial responses. Blocking CXCL12/CXCR4 may be a potential therapeutic approach for PD progression.

scholarly journals Differential Changes in Postsynaptic Density Proteins in Postmortem Huntington’s Disease and Parkinson’s Disease Human Brains

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
C. Fourie ◽  
E. Kim ◽  
H. Waldvogel ◽  
J. M. Wong ◽  
A. McGregor ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Immunohistochemical Analysis ◽  
Synaptic Proteins ◽  
Postmortem Brain ◽  
Postmortem Brain Tissue ◽  
Human Brains

NMDA and AMPA-type glutamate receptors and their bound membrane-associated guanylate kinases (MAGUKs) are critical for synapse development and plasticity. We hypothesised that these proteins may play a role in the changes in synapse function that occur in Huntington’s disease (HD) and Parkinson’s disease (PD). We performed immunohistochemical analysis of human postmortem brain tissue to examine changes in the expression of SAP97, PSD-95, GluA2 and GluN1 in human control, and HD- and PD-affected hippocampus and striatum. Significant increases in SAP97 and PSD-95 were observed in the HD and PD hippocampus, and PSD95 was downregulated in HD striatum. We observed a significant increase in GluN1 in the HD hippocampus and a decrease in GluA2 in HD and PD striatum. Parallel immunohistochemistry experiments in the YAC128 mouse model of HD showed no change in the expression levels of these synaptic proteins. Our human data show that major but different changes occur in glutamatergic proteins in HD versus PD human brains. Moreover, the changes in human HD brains differ from those occurring in the YAC128 HD mouse model, suggesting that unique changes occur at a subcellular level in the HD human hippocampus.

scholarly journals scREAD: A single-cell RNA-Seq database for Alzheimer’s Disease

2020 ◽  
Author(s):  
Jing Jiang ◽  
Cankun Wang ◽  
Ren Qi ◽  
Hongjun Fu ◽  
Qin Ma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Neurodegenerative Disorder ◽  
Supplementary Information ◽  
Cell Type ◽  
Link Type ◽  
Postmortem Brain Tissue ◽  
The Brain

AbstractSummaryAlzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain and the most common form of dementia among the elderly. The single-cell RNA-sequencing (scRNA-Seq) and single-nucleus RNA-sequencing (snRNA-Seq) techniques are extremely useful for dissecting the function/dysfunction of highly heterogeneous cells in the brain at the single-cell level, and the corresponding data analyses can significantly improve our understanding of why particular cells are vulnerable in AD. We developed an integrated database named scREAD (single-cell RNA-Seq database for Alzheimer’s Disease), which is the first database dedicated to the management of all the existing scRNA-Seq and snRNA-Seq datasets from human postmortem brain tissue with AD and mouse models with AD pathology. scREAD provides comprehensive analysis results for 55 datasets from eight brain regions, including control atlas construction, cell type prediction, identification of differentially expressed genes, and identification of cell-type-specific regulons.Availability and ImplementationscREAD is a one-stop and user-friendly interface and freely available at https://bmbls.bmi.osumc.edu/scread/. The backend workflow can be downloaded from https://github.com/OSU-BMBL/scread/tree/master/script, to enable more discovery-driven [email protected] or [email protected] informationSupplementary data are available at Bioinformatics online.

scholarly journals APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jon-Anders Tunold ◽  
Hanneke Geut ◽  
J. M. Annemieke Rozemuller ◽  
Sandra Pilar Henriksen ◽  
Mathias Toft ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Proportional Hazards ◽  
Age At Onset ◽  
Cox Proportional Hazards ◽  
Postmortem Brain ◽  
Tissue Samples ◽  
Postmortem Brain Tissue ◽  
Ε4 Allele

Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia.Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia.Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease.Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.

Identification of Parkinson's disease biomarkers through RNA sequencing of peripheral blood leukocytes

2021 ◽  
Vol 429 ◽  
pp. 119469
Author(s):  
Valentina Tommasini ◽  
Mauro Catalan ◽  
Maurizio Romano ◽  
Giulia Mazzon ◽  
Tatiana Cattaruzza ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rna Sequencing ◽  
Peripheral Blood ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
Disease Biomarkers

Critical downstream analysis steps for single-cell RNA sequencing data

2021 ◽  
Author(s):  
Zilong Zhang ◽  
Feifei Cui ◽  
Chen Lin ◽  
Lingling Zhao ◽  
Chunyu Wang ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Noisy Data ◽  
Single Cell Level ◽  
Cell Type ◽  
Sequencing Data ◽  
Cell Level ◽  
Bioinformatics Tool ◽  
Single Cell Rna Sequencing ◽  
Downstream Analysis

Abstract Single-cell RNA sequencing (scRNA-seq) has enabled us to study biological questions at the single-cell level. Currently, many analysis tools are available to better utilize these relatively noisy data. In this review, we summarize the most widely used methods for critical downstream analysis steps (i.e. clustering, trajectory inference, cell-type annotation and integrating datasets). The advantages and limitations are comprehensively discussed, and we provide suggestions for choosing proper methods in different situations. We hope this paper will be useful for scRNA-seq data analysts and bioinformatics tool developers.

scholarly journals Single-cell RNA sequencing of the mammalian pineal gland identifies two pinealocyte subtypes and cell type-specific daily patterns of gene expression

PLoS ONE ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. e0205883 ◽  
Author(s):  
Joseph C. Mays ◽  
Michael C. Kelly ◽  
Steven L. Coon ◽  
Lynne Holtzclaw ◽  
Martin F. Rath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pineal Gland ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cell Type ◽  
Single Cell Rna Sequencing ◽  
Cell Type Specific ◽  
Mammalian Pineal Gland ◽  
Daily Patterns

scholarly journals Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3547
Author(s):  
Srinivasa Reddy Bonam ◽  
Christine Tranchant ◽  
Sylviane Muller
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Cell Survival ◽  
Control Systems ◽  
Therapeutic Strategies ◽  
Cell Type ◽  
Potential Therapeutic Target ◽  
Cellular Components

Cellular quality control systems have gained much attention in recent decades. Among these, autophagy is a natural self-preservation mechanism that continuously eliminates toxic cellular components and acts as an anti-ageing process. It is vital for cell survival and to preserve homeostasis. Several cell-type-dependent canonical or non-canonical autophagy pathways have been reported showing varying degrees of selectivity with regard to the substrates targeted. Here, we provide an updated review of the autophagy machinery and discuss the role of various forms of autophagy in neurodegenerative diseases, with a particular focus on Parkinson’s disease. We describe recent findings that have led to the proposal of therapeutic strategies targeting autophagy to alter the course of Parkinson’s disease progression.

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