Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression

Mariani, Elisa; Frabetti, Flavia; Tarozzi, Andrea; Pelleri, Maria Chiara; Pizzetti, Fabrizio; Casadei, Raffaella

doi:10.1371/journal.pone.0161567

Cited by 56 publications

(57 citation statements)

References 66 publications

(84 reference statements)

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“…Downregulation of PARK and non‐PARK parkinsonism genes is likely to affect multiple key biological processes and may lead to dopaminergic neuronal death in PD. Of note, we observed a downregulation of PPP2R2B in all nine GWESs, and this behavior has not been previously shown except for a recent study using transcriptome mapping software . An expanded CAG repeat in the promoter region of PPP2R2B is causative for SCA12 .…”

Section: Discussionsupporting

confidence: 63%

“…Of note, we observed a downregulation of PPP2R2B in all nine GWESs, and this behavior has not been previously shown except for a recent study using transcriptome mapping software. 45 An expanded CAG repeat in the promoter region of PPP2R2B is causative for SCA12. 46 In unstable repeat disorders, a loss of function because of the inhibition of transcription and the gain-of-toxic function mutation because of expanded polyglutamine tracks or toxic RNA are well-documented mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease

et al. 2017

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease

et al. 2017

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“…The current understanding of the molecular mechanisms behind initiation and progression of Parkinson's disease (PD) is still limited. Previous molecular studies on human post-mortem brain tissues mostly stem from late stages of PD [33,62], making it difficult to infer causality between molecular events and pathological outcome. In addition, long post-mortem delays, several comorbidities and high inter-individual variations complicate the interpretation of molecular data.…”

Section: Introductionmentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

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“…In addition, we next focused our attention in determining if these alterations might also be found on other neurodegenerative conditions independently on the analyzed brain region. After extensive meta-analysis, we only found alterations at mRNA level for AZGBP1 and ALPP in Parkinson’s disease [ 47 ], and LGALS3BP in Lewy body dementia [ 48 ]; and thus, suggesting that the deregulated proteins identified in our study were mostly specific of AD.…”

Section: Resultsmentioning

confidence: 94%

Identification of prefrontal cortex protein alterations in Alzheimer’s disease

et al. 2018

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Alzheimer’s disease (AD) is the most common form of dementia in developed countries. A better understanding of the events taking place at the molecular level would help to identify novel protein alterations, which might be used in diagnosis or for treatment development. In this study, we have performed the high-throughput analysis of 706 molecules mostly implicated in cell-cell communication and cell signaling processes by using two antibody microarray platforms.We screened three AD pathological groups -each one containing four pooled samples- from Braak stages IV, V and VI, and three control groups from two healthy subjects, five frontotemporal and two vascular dementia patients onto Panorama and L-Series antibody microarrays to identify AD-specific alterations not common to other dementias. Forty altered proteins between control and AD groups were detected, and validated by i) meta-analysis of mRNA alterations, ii) WB, and iii) FISH and IHC using an AD-specific tissue microarray containing 44 samples from AD patients at different Braak stages, and frontotemporal and vascular dementia patients and healthy individuals as controls.We identified altered proteins in AD not common to other dementias like the E3 ubiquitin-protein ligase TOPORS, Layilin and MICB, and validated the association to AD of the previously controverted proteins DDIT3 and the E3 ubiquitin-protein ligase XIAP. These altered proteins constitute interesting targets for further immunological analyses using sera, plasma and CSF to identify AD blood- or cerebrospinal fluid-biomarkers and to perform functional analysis to determine their specific role in AD, and their usefulness as potential therapeutic targets of intervention.

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Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression

Cited by 56 publications

References 66 publications

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Identification of prefrontal cortex protein alterations in Alzheimer’s disease

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