Hong Kong University of Science and Technology, Hong Kong
Abstract: The accumulation of cellular damage, characterized by aging hallmarks, renders the brain increasingly vulnerable to neurological diseases. This process exhibits region-specificity, as evidenced by the early manifestation of age-related diseases in certain brain regions but not in others. For instance, the cortex and hippocampus show early plaque pathology in Alzheimer’s disease. Previous studies have reported both global and cell-type-specific transcriptomic alterations, raising questions about whether transcriptional regulation is disrupted during aging.
Here, we constructed a single-nuclei atlas of the cortex, hippocampus, and cerebellum to identify region-specific transcriptional alterations at both the gene and isoform levels. Using an in situ sequencing method, SPRINTseq, we incorporated spatial information on differential gene and isoform expression. Our analysis revealed broad expression changes in histone acetylases and RNA-binding proteins involved in splicing regulation.
In neurons, isoform-level analysis from full-length scRNA-seq uncovered isoform usage switches and intron retention in genes involved in critical biological pathways, such as mRNA splicing, synaptic function, and axon projection. Such dysregulation may lead to nonsense-mediated decay of transcripts or the production of truncated proteins, disrupting cellular homeostasis.
