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Common gene expression signatures in Parkinson's disease are driven by changes in cell composition
Gonzalo S Nido1,2, Fiona Dick1,2, Lilah Toker1,2
1Neuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway.
Acta Neuropathologica Communications
|April 23, 2020
Summary
Parkinson's disease transcriptomic studies are confounded by cell type differences. Accounting for cell type heterogeneity reveals endoplasmic reticulum and unfolded protein response pathways as key signatures in Parkinson's disease brain tissue.
Area of Science:
- Neuroscience
- Genomics
- Molecular Biology
Background:
- Genome-wide transcriptomic studies in bulk brain tissue have identified molecular signatures linked to Parkinson's disease (PD).
- However, these studies are limited by RNA post-mortem degradation and heterogeneous cell type composition in bulk tissue samples.
- Understanding the etiology of Parkinson's disease remains a significant challenge.
Purpose of the Study:
- To investigate the impact of cell type composition on differential gene expression analysis in Parkinson's disease prefrontal cortex.
- To identify robust transcriptomic signatures associated with Parkinson's disease pathogenesis by controlling for cell type heterogeneity.
- To compare RNA sequencing library preparation methods for post-mortem brain tissue.
Main Methods:
- Performed RNA sequencing on prefrontal cortex samples from 49 individuals across two independent case-control cohorts.
- Utilized ribosomal RNA depletion for enhanced transcript coverage in post-mortem tissue.
- Estimated cell type composition using specific markers and incorporated it into differential gene expression models.
Main Results:
- Ribosomal RNA depletion provided more even transcript coverage compared to poly(A) capture in post-mortem samples.
- Cell type composition was identified as a major confounder in Parkinson's disease differential gene expression analysis.
- Accounting for cell type proportions attenuated previously reported signatures (e.g., vesicle trafficking, synaptic transmission) and strengthened others (e.g., endoplasmic reticulum, unfolded protein response).
Conclusions:
- Differential gene expression signatures in bulk Parkinson's disease brain tissue are significantly influenced by cell type composition.
- Modeling cell type heterogeneity is critical for uncovering true regulatory changes and underlying disease mechanisms in Parkinson's disease.
- This approach refines the understanding of molecular pathology in Parkinson's disease.
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