Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes

Abstract

Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identified several molecular mechanisms as autophagy and inflammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specific transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specific transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes first occur in the sampled brain region. Additionally, we identified disease stage-specific enrichment of brain specific pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stage-specific, which has major implications for the study of neurodegenerative disorders.

Nigral transcriptomic profiles in Engrailed-1 hemizygous mouse models of Parkinson’s disease reveal upregulation of oxidative phosphorylation-related genes associated with delayed dopaminergic neurodegeneration

“…The consistent detection of differential gene expression of mitochondrial genes and genes that code for proteins in the OxPhos chain is likely to have functional impact, given the strong evidence linking mitochondrial impairment and energy metabolism to PD. This includes mitochondrial effects on progression and pathogenesis of PD models in different organisms ( Briston and Hicks, 2018 ; Ordonez et al, 2018 ; Ikuno et al, 2021 ; Murali Mahadevan et al, 2021 ), the toxic effects of MPTP and Rotenone, a reduced activity of complex I in postmortem PD brains ( Cappelletti et al, 2023 ) and the association between PD genes and mitochondria ( Rekaik et al, 2015a ). In addition, inhibition of the mitochondrial pyruvate carrier has been shown to directly slow down pyruvate oxidation in isolated brain mitochondria, to increase the utilization of other substrates, to normalize oxygen consumption after MPP+ treatment, to reduce dopaminergic neurodegeneration in vitro and in vivo , and well as to reduce motor impairment in OF1- En1 +/− mice ( Ghosh et al, 2016 ).…”

A systematic exploration of unexploited genes for oxidative stress in Parkinson’s disease

“…Because existing meta-analyses that have delineated DEGs associated with PD, we curated and compiled PD-DEG sets from three relevant studies [36][37][38] (Table 2). These studies performed metaanalyses of PD transcriptomic data to derive robust gene expression signatures for the disease.…”

“…Additionally, PD-associated genes identified through TWAS in the brain tissue were obtained from the TWAS-Atlas database 39 and incorporated. In total, the PD-DEG comprised 2,895 unique genes (1,378 from PMID:27611585 36 , 585 from PMID: 33390883 37 , 989 from PMID: 37347276 38 , and 196 from the TWAS-Atlas) [Figure 2]. Gene set enrichment analysis (GSEA) confirmed the signature of the PD-DEG compilation, with the most enriched term as "has05012: Parkinson disease" [Figure 3a].…”

Transcriptomics of Human Brain Tissue in Parkinson’s Disease: a Comparison of Bulk and Single-cell RNA Sequencing

“…Bulk RNA-seq analyses of the midbrain [45], prefrontal cortex [51], and frontal cortex [55] have all identified transcriptional evidence for inflammatory pathways in PD samples. The strongest signal was derived from the midbrain, as bulk RNA-seq disclosed that approximately half of the DEGs between PD samples and non-PD controls were related to the immune-inflammatory response [45].…”

“…In contrast, an activated inflammatory response in the PD prefrontal cortex was inferred by bulk RNA-seq through significant increases in microglia and oligodendrocyte marker gene profiles compared to non-PD controls, without any differential gene expression to suggest an elevated inflammatory response in PD [51]. In the frontal cortex, Cappelletti et al leveraged bulk RNA-seq data from 84 samples, allowing them to maintain power upon stratifying the PD samples into three groups according to their degree of Lewy body pathology-based on the Braak Lewy body stage-which was used as a proxy for disease progression [55]. In doing so, the authors observed that immune response pathways were upregulated at early disease stages and downregulated at the most advanced stage [55].…”