A co‐expression network based molecular characterization of genes responsive for Braak stages in Parkinson's disease

• Published in: The European journal of neuroscience 2022-04, Vol.55 (7), p.1873-1886
• Main Authors: Düz, Elif, Çakır, Tunahan
• Format: Article
• Language: English
• Subjects: Braak stage; co‐expression network analysis; Energy metabolism; Humans; Mitochondria; Molecular modelling; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurons; Oxidative metabolism; Oxidative phosphorylation; Parkinson Disease - genetics; Parkinson's disease; Phosphorylation; Proteasomes; Seizures; Signal transduction; Synaptic transmission; Synuclein; Transcriptome; Transcriptomes; Tricarboxylic acid cycle; Tubulin
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15653

The progression of Parkinson's disease (PD) is defined by six Braak stages. We used transcriptome data from PD patients with Braak stage information to understand underlying molecular mechanisms for the progress of the disease. We created networks of genes with continuously decreased/increased co‐expression from control group to Braak 5–6 stages. These networks are significantly associated with PD‐related mechanisms such as mitochondrial dysfunction and synaptic signalling among others. Applying weighted gene co‐expression network analysis (WGCNA) algorithm to the co‐expression networks led to more specific modules enriched with neurodegeneration‐related disease pathways, seizure, abnormality of coordination, and hypotonia. Furthermore, we showed that one of the co‐expression networks is clustered into three major communities with dedicated molecular functions: (i) tubulin folding pathway, gap junction‐related mechanisms, neuronal system; (ii) synaptic vesicle, intracellular vesicle, proteasome complex, PD genes; (iii) energy metabolism, mitochondrial mechanisms, oxidative phosphorylation, TCA cycle, PD genes. The co‐expression relations we identified in this study as crucial players in the disease progression cover several known PD‐associated genes and genes whose products are known to physically interact with alpha‐synuclein protein. Here, we used a unique Parkinson's disease transcriptome dataset that reports mRNA expression data from substantia nigra region of postmortem brains in different categories: Control, Braak 1–2, Braak 3–4, and Braak 5–6. We identified genes that show continuously decreasing/increasing co‐expression as the disease progresses from control to Braak 5–6 stages. We show that the identified co‐expression networks are relevant because they are significantly enriched with genes playing roles in PD‐related mechanisms such as mitochondrial dysfunction and synaptic signalling among others. The genes in the networks with no known Parkinson's disease association are strong candidate genes