AUTHOR=Christodoulou Christiana C. , Onisiforou Anna , Zanos Panos , Papanicolaou Eleni Zamba 

TITLE=Unraveling the transcriptomic signatures of Parkinson’s disease and major depression using single-cell and bulk data

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 15 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1273855

DOI=10.3389/fnagi.2023.1273855

ISSN=1663-4365

ABSTRACT=Motor symptoms are well-characterized in Parkinson's Disease (PD). However, non-motor symptoms (depression), are observed and appear up to 10 years before motor features, resulting in one-third of individuals being misdiagnosed with a neuropsychiatric disorder. Thus, identifying diagnostic biomarkers is crucial for accurate PD diagnosis during its prodromal or early stages. We employed an integrative approach, combining single nucleus RNA and bulk mRNA transcriptomics to perform comparative molecular signatures analysis between PD and Major Depressive Disorder (MDD). We examined 39,834 nuclei from PD (GSE202210) and 32,707 nuclei from MDD (GSE144136) in the dorsolateral prefrontal cortex (dlPFC) of Brodmann area 9. Additionally, we analyzed bulk mRNA peripheral blood samples from PD compared to controls (GSE49126, GSE72267), as well as MDD compared to controls (GSE39653). Our findings show a higher proportion of astrocytes and oligodendrocytes in the dlPFC of PD vs MDD individuals. The excitatory to inhibitory neurons (E/I) ratio indicates MDD has a ratio close to normal 80/20, while PD has a ratio of 62/38, indicating increased inhibition in the dlPFC. Microglia displayed a pronounced difference in gene expression profiles between the two conditions. In PD, microglia display a pro-inflammatory phenotype, while in MDD, they regulate synaptic transmission through oligodendrocyte-microglia crosstalk. Analysis of bulk mRNA blood samples revealed COL5A, MID1, ZNF148, and CD22 genes were highly expressed in PD, whereas the DENR and RNU1G2 genes were highly expressed in MDD. CD22 is involved in B-cell activation and the negative regulation of B-cell receptor signaling. Additionally, CD86, which provides co-stimulatory signals for T-cell activation and survival, was found to be a commonly differentially expressed gene in both conditions. Pathway analysis revealed several immune-related pathways common in both conditions, including the complement and coagulation cascade, and B-cell receptor signaling. This study shows that bulk peripheral immune cells are involved in both conditions, but neuroinflammation is specifically present in PD based on analysis of single nucleus dlPFC cells. Integrating these two omics offers a better understanding of shared and distinct molecular pathophysiology of PD and MDD in the periphery and brain. These findings could lead to potential diagnostic biomarkers, improving accuracy and guiding pharmacological treatments.