Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis

Capurro, Alberto; Bodea, Liviu‐Gabriel; Schaefer, Patrick; Lüthi-Carter, Ruth; Perreau, Victoria M.

doi:10.3389/fnins.2014.00441

Cited by 31 publications

(29 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observed gene expression profiles in bulk brain tissue can be dramatically influenced by differences in cellular composition. Such differences can be a result of variation in gray/white matter ratios introduced during tissue extraction, inter-subject variability or represent disease related alterations [14][15][16]. To study the contribution of various technical and biological sources of variation in our dataset we first estimated marker gene profiles (MGPs) for the major classes of cortical cell types (astrocytes, microglia, oligodendrocytes, and neurons) in our samples by summarizing the expression of the cell type-specific marker genes as previously described [15].…”

Section: Cell Composition Is a Major Confounder Of Gene Expression Inmentioning

confidence: 99%

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

Nido

Dick

Toker

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractBackgroundThe etiology of Parkinson’s disease (PD) is largely unknown. Genome-wide transcriptomic studies in bulk brain tissue have identified several molecular signatures associated with the disease. While these studies have the potential to shed light into the pathogenesis of PD, they are also limited by two major confounders: RNA post mortem degradation and heterogeneous cell type composition of bulk tissue samples. We performed RNA sequencing following ribosomal RNA depletion in the prefrontal cortex of 49 individuals from two independent case-control cohorts. Using cell-type specific markers, we estimated the cell-type composition for each sample and included this in our analysis models to compensate for the variation in cell-type proportions.ResultsRibosomal RNA depletion results in substantially more even transcript coverage, compared to poly(A) capture, in post mortem tissue. Moreover, we show that cell-type composition is a major confounder of differential gene expression analysis in the PD brain. Correcting for cell-type proportions attenuates numerous transcriptomic signatures that have been previously associated with PD, including vesicle trafficking, synaptic transmission, immune and mitochondrial function. Conversely, pathways related to endoplasmic reticulum, lipid oxidation and unfolded protein response are strengthened and surface as the top differential gene expression signatures in the PD prefrontal cortex.ConclusionsDifferential gene expression signatures in PD bulk brain tissue are significantly confounded by underlying differences in cell-type composition. Modeling cell-type heterogeneity is crucial in order to unveil transcriptomic signatures that represent regulatory changes in the PD brain and are, therefore, more likely to be associated with underlying disease mechanisms.

show abstract

Section: Cell Composition Is a Major Confounder Of Gene Expression Inmentioning

confidence: 99%

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

Nido

Dick

Toker

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…200 A recent computational analysis involving genome wide expression data from Parkinson and Huntington disease brain tissue was entirely consistent with the importance of autophagy in these disease processes. 203 …”

Section: Therapeutic Modulation Of Pqc To Curtail Proteotoxicitymentioning

confidence: 99%

Proteotoxicity and Cardiac Dysfunction

McLendon

Robbins

2015

Circulation Research

View full text Add to dashboard Cite

Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.

show abstract

“…This gene has also been shown to be associated with different neurodegenerative disorders including PD [Lencz et al., ; Liu et al., ]. Furthermore, previous studies have shown that expression of NSF is decreased in PD substantia nigra [Simunovic et al., ; Elstner et al., ; Capurro et al., ].These data may indicate that the rs897984 mutant allele influences the risk of PD through reducing the level of miR‐4519 and increasing the expression of NSF gene.…”

Section: Discussionmentioning

confidence: 98%

Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease

et al. 2015

View full text Add to dashboard Cite

MicroRNAs (miRNAs) are small noncoding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA-binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA-related genetic variants with Parkinson disease (PD) using data from the largest GWAS on PD. Of 243 miRNA variants, we identified rs897984:T>C in miR-4519 (P value = 1.3×10(-5) and OR = 0.93) and rs11651671:A>G in miR-548at-5p (P value = 1.1×10(-6) and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR-4519 and miR-548at-5p on PD. Among them, we experimentally showed that NSF is a direct target of miR-4519. Furthermore, among 48,844 miRNA-binding site variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B, and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA-binding site variants on miRNA-mediated regulation of their host genes.

show abstract

Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis

Cited by 31 publications

References 72 publications

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

Proteotoxicity and Cardiac Dysfunction

Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease

Contact Info

Product

Resources

About