Lukas Iohan, Brazil
Federal University of Rio Grande do Norte Brain InstituteAuthor Of 1 Presentation
GENE ISOFORM SWITCHING IS A HALLMARK OF ALZHEIMER'S AND OTHER AGING-ASSOCIATED DISEASES
Abstract
Aims
In this work, we aimed at the identification of gene isoform switches in the brain of healthy and Alzheimer’s disease (AD) adult subjects using data from three large studies: Mayo Clinic; Mount Sinai Brain Bank (MSBB) and Religious Orders Study and Memory and Aging Project ROSMAP. We also evaluated isoform switches in two other aging-associated conditions: Progressive supranuclear palsy (PSP) and pathologic aging (PA).
Methods
We used DSeq2 and ISAR to identify gene expression alterations in RNAseq data generated from samples of different brain regions of healthy, AD, PSP and PA subjects. Next, we used scRNAseq to assign altered genes to unique cell types of the adult human brain.
Results
We show that isoform switches are a hallmark of AD, PSP and PA, allowing the identification of gene expression alterations overlooked in classical differential gene expression analyses. Importantly, several gene expression alterations identified by isoform switch analyses are associated with key pathological processes in the brain of AD, PSP and PA subjects. Finally, we also demonstrate a positive correlation between isoform switches and changes in the expression of splicing-associated genes in neuronal cells, suggesting that alternative splicing is altered in the diseased brain.
Conclusions
Our data indicate that isoform switches are an important source of gene expression alteration in the aging brain and might be associated with several biological processes affected in neurodegenerative conditions. Our results also suggest that altered alternative splicing could be a common mechanism in AD and other aging-related diseases.