Identification of exon-skipping splicing alterations associated with Alzheimer’s disease and progressive supranuclear palsy

Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are neurodegenerative tauopathies characterized by accumulation of insoluble hyperphosphorylated tau protein in the brain. Despite neuropathological similarities, these conditions are also differentiated by distinct pathological and clinical features informed by complex molecular mechanisms. Therefore, exploring the molecular mechanisms that are conserved or distinct in AD and PSP is crucial for understanding the pathogenic risk factors contributing to these conditions and will ultimately advance preventive strategies in precision medicine. Although alternative splicing is among the most important forms of transcriptional regulation in the brain, its role in distinguishing or unifying mechanisms between these conditions remains incompletely understood. Transcriptomic analysis was performed on RNA-seq data from the temporal cortex of 82 AD patients, 84 PSP patients, and 78 controls in the discovery set, and 96 AD and 96 PSP patients in the replication set. Differential exon skipping events in AD and PSP were identified, followed by functional enrichment analysis. Whole-genome sequencing (WGS) data from ascertained samples were further integrated to investigate their cis-genetic regulators as splicing quantitative trait loci (sQTLs). Relative to the controls, a total of 472 and 366 genes with exon skipping events (ES genes) were differentially spliced in AD and PSP, respectively. Among these, 325 ES genes were specific to AD and 219 to PSP, while 147 ES genes were common to both conditions. These shared ES genes were enriched in pathways related to neural activity and tau metabolism such as myelination, Schwann cell development, and neurotrophin production. ES genes exclusive to AD were enriched for synaptic activity, lipid metabolism, and amyloid beta processing, and those exclusive to PSP for the vesicle-mediated transport pathway. Further integration of WGS data identified three independent splicing quantitative trait loci ( cis -sQTLs) that were associated with three ES events in the genes c7orf63 , DEF8 , and HAP1 . This study highlights common and distinct molecular mechanisms mediated through exon skipping that underlie the tauopathies, AD and PSP. These findings enhance our understanding of the complex neuropathogenic mechanisms associated with these conditions and ultimately support further research aimed at identifying and developing effective treatment strategies.