The central nervous system (CNS) is highly complex due to its wide variety of cell types. Based on a handful of molecular markers, cell shape, and function, traditional classifications often miss the subtle molecular differences within cell types. RNA, which translates genetic information from DNA into functional building blocks in the cell, plays a key role in CNS cell type diversity. Single-cell RNA sequencing allows us to capture the "fingerprints" of individual cells with high resolution. Spatial RNA sequencing adds a spatial dimension, helping us understand how gene expression differs in healthy and diseased brain tissue. Understanding the diversity of the healthy brain and its disruptions in CNS diseases can reveal dysregulated molecular mechanisms and guide the development of future therapies.
This thesis of Astrid Alsema investigates the subpopulations and transcriptional diversity of neurons and brain vasculature cells in the human midbrain using single-cell RNA sequencing. In donors with schizophrenia, no major gene expression changes were observed in the cell types of the blood-brain barrier, but subtle gene expression differences were found in specific GABAergic neurons.
Additionally, this thesis focuses on multiple sclerosis (MS), a CNS disease marked by focal lesions and spatially distinct pathology, through spatial RNA sequencing. Unique gene expression patterns were identified at the edges of active MS lesions. Astrocytes, oligodendrocytes, and microglia show altered gene expression activity in these areas, highlighting their importance in disease progression. This research provides insights into molecular changes in schizophrenia and MS, forming hypotheses on temporal gene expression changes, crucial for developing new therapies.
