Christodoulou Christiana C, Onisiforou Anna, Zanos Panos, Papanicolaou Eleni Zamba
Neuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
The Cyprus Institute of Neurology and Genetics Is a Full Member of the European Reference Network-Rare Neurological Diseases (ERN-RND), Tübingen, Germany.
Front Aging Neurosci. 2023 Nov 7;15:1273855. doi: 10.3389/fnagi.2023.1273855. eCollection 2023.
Motor symptoms are well-characterized in Parkinson's disease (PD). However, non-motor symptoms, such as depression, are commonly observed and can 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 oligodendrocyte cells in the dlPFC of individuals with PD vs. MDD. The excitatory to inhibitory neurons (E/I) ratio analysis indicates that 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 the most pronounced differences 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 that the , , , and genes were highly expressed in PD, whereas the and genes were highly expressed in MDD. is involved in B-cell activation and the negative regulation of B-cell receptor signaling. Additionally, , 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 demonstrates that bulk peripheral immune cells play a role in both conditions, but neuroinflammation in the dlPFC specifically manifests in PD as evidenced by the analysis of single nucleus dlPFC datasets. Integrating these two omics levels offers a better understanding of the shared and distinct molecular pathophysiology of PD and MDD in both the periphery and the brain. These findings could lead to potential diagnostic biomarkers, improving accuracy and guiding pharmacological treatments.
帕金森病（PD）的运动症状已得到充分表征。然而，非运动症状，如抑郁症，也很常见，并且可能在运动特征出现前10年就出现，导致三分之一的个体被误诊为神经精神疾病。因此，识别诊断生物标志物对于在PD前驱期或早期进行准确诊断至关重要。
我们采用了一种综合方法，将单核RNA和大量mRNA转录组学相结合，以对PD和重度抑郁症（MDD）进行比较分子特征分析。我们检查了布罗德曼区9背外侧前额叶皮质（dlPFC）中来自PD（GSE202210）的39834个细胞核和来自MDD（GSE144136）的32707个细胞核。此外，我们分析了与对照组相比PD的大量mRNA外周血样本（GSE49126，GSE72267），以及与对照组相比MDD的大量mRNA外周血样本（GSE39653）。
我们的研究结果表明，与MDD患者相比，PD患者dlPFC中的星形胶质细胞和少突胶质细胞比例更高。兴奋性与抑制性神经元（E/I）比率分析表明，MDD的比率接近正常的80/20，而PD的比率为62/38，表明dlPFC中的抑制作用增强。小胶质细胞在两种情况下的基因表达谱差异最为明显。在PD中，小胶质细胞表现出促炎表型，而在MDD中，它们通过少突胶质细胞 - 小胶质细胞串扰调节突触传递。对大量mRNA血样的分析表明， 、 、 和 基因在PD中高度表达，而 和 基因在MDD中高度表达。 参与B细胞活化和B细胞受体信号的负调节。此外， 为T细胞活化和存活提供共刺激信号，被发现是两种情况下共同差异表达的基因。通路分析揭示了两种情况下常见的几种免疫相关通路，包括补体和凝血级联反应以及B细胞受体信号传导。
本研究表明，大量外周免疫细胞在两种情况下都起作用，但通过对单核dlPFC数据集的分析证明，dlPFC中的神经炎症在PD中特异性表现。整合这两个组学水平有助于更好地理解PD和MDD在外周和大脑中共同和独特的分子病理生理学。这些发现可能会产生潜在的诊断生物标志物，提高诊断准确性并指导药物治疗。
