Transcriptomics in Neurodegenerative Disease

Abstract

Alzheimer’s (AD) and Parkinson’s (PD) are primary neurodegenerative diseases (NDs) worldwide. Their complex mechanisms, illuminated by neuropathological studies and modern biomedical tools, call for non-invasive biomarkers, preferably from blood, for early detection, differentiating from regular aging.

Omics advancements, especially genomics and transcriptomics, have deepened our molecular understanding of NDs, helping segregate patients based on distinct molecular attributes and refining biomarker clarity.

Our research used RNA sequencing (RNA-seq) to analyze transcriptomes from the dorsolateral prefrontal cortex (DLPFC/BA9), whole blood (WB), and peripheral blood mononuclear cells (PBMC) using data from the Sequence Read Archive (SRA), negating in-house sequencing. With single nucleotide polymorphisms (SNPs), we explored shared pathological occurrences between AD and PD, investigating if ND brain molecular routes manifest in blood.

Applying differential gene expression and a random forest machine-learning technique, our data revealed a scarce overlap between AD and PD. Noteworthy AD markers like Mef2C in AD-DLPFC/BA9 and TMED7 were identified. AD blood markers emphasized cilia-driven TLR4/NF-κB activation and Fyn. In PD, SNARE proteins, e.g., VAMP2 and STX1A, suggested connections between α-syn and SNARE protein reshuffling, implicating synaptic malfunction.

Genome-wide association studies (GWAS) affirmed certain discoveries. Both NDs showed overlaps in the brain and blood. Mainly, VEGF-A and inositol polyphosphates (InsPs) were detected. AD blood samples chiefly exhibited elements tied to Aβ aggregation and tau irregularities.

Further, eQTL and sQTL mapping illuminated the roles of GWAS-associated markers in AD and PD susceptibility, with shifts in gene expression and splicing events affecting both NDs.

The present work emphasizes harnessing GWAS and QTL data to decipher ND complexities, urging continued research for therapeutic ND solutions.