2021
DOI: 10.1007/s00401-021-02343-x
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Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

Abstract: Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can … Show more

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Cited by 44 publications
(66 citation statements)
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References 133 publications
(235 reference statements)
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“…Oligodendrocyte-specific proteins, such as the myelinating proteins MBP, MOG, MOBP, PLP, OMG, MPM2, and CNP, are also downregulated across disease stages, including in unaffected regions by > 1.5 fold compared to controls. This alteration in oligodendrocyte-specific proteins in 'yet to be affected' regions in PD brains, supports recent transcriptomic studies implicating oligodendrocyte dysfunction as an early and important event in PD [82][83][84]. The reduction in sirtuin-2 in early PD may therefore (i) be linked to oligodendrocyte dysfunction and represent an early mechanism by which mitochondrial metabolism and oxidative stress occurs, or (ii) may in some way be linked to a protective mechanism against, and prior to the emergence of, alpha-synuclein aggregation.…”
Section: Identifying Common Pathways Across Early Pd Brainsupporting
confidence: 83%
“…Oligodendrocyte-specific proteins, such as the myelinating proteins MBP, MOG, MOBP, PLP, OMG, MPM2, and CNP, are also downregulated across disease stages, including in unaffected regions by > 1.5 fold compared to controls. This alteration in oligodendrocyte-specific proteins in 'yet to be affected' regions in PD brains, supports recent transcriptomic studies implicating oligodendrocyte dysfunction as an early and important event in PD [82][83][84]. The reduction in sirtuin-2 in early PD may therefore (i) be linked to oligodendrocyte dysfunction and represent an early mechanism by which mitochondrial metabolism and oxidative stress occurs, or (ii) may in some way be linked to a protective mechanism against, and prior to the emergence of, alpha-synuclein aggregation.…”
Section: Identifying Common Pathways Across Early Pd Brainsupporting
confidence: 83%
“…Findings of current gene expression studies further point out the involvement of microglia in the pathophysiology of PD/DLB [75,76]. Compared to healthy control brains, single-cell RNA sequencing discovered an enhancement of the microglia fraction in the anterior cingulate cortex of DLB and PD [75] patients, as well as in the PD midbrain [76]. In addition, microglia of the idiopathic PD midbrain contain subpopulations that are enriched towards an activated state [76].…”
Section: Microglia-mediated Neuroinflammation In Pd and Dlbmentioning
confidence: 77%
“…The meta-analysis used bulk transcriptomics data, and the relative proportions of cell types may therefore differ between the compared sample groups. Prior studies have shown that differential gene expression patterns derived from PD bulk transcriptomics datasets of cortical tissues can be confounded by cell type composition differences 42 , 43 . To estimate how this could affect our differential analysis, we analyzed the differential expression profiles of 38 selected cell type markers corresponding to 5 distinct brain cell types (more details about the markers can be found in Supplementary Note 1 , Supplementary Table 13 , and Supplementary Figs.…”
Section: Resultsmentioning
confidence: 99%