Perez-Cerda, F. | Search bioRxiv

bioRxiv2024

TAF1-dependent transcriptional dysregulation underlies multiple sclerosis

A major conceptual and clinical challenge in multiple sclerosis (MS) is understanding the mechanisms that drive the central nervous system (CNS)-resident neuroinflammation and neurodegeneration underneath disease progression. Genome-wide association studies (GWAS) have implicated RNA polymerase II (RNAPII) promoter-proximal pausing in oligodendrocyte pathology, but the causal mechanisms remain unclear. Here we find that the C-terminal region of TAF1, a core component of the general transcription factor TFIID, is underdetected in progressive MS brains, which can be explained by endoproteolysis due to extralysosomal cathepsin B (CTSB). Mice lacking the C-terminal TAF1 domain (Taf1d38) exhibit MS-like brain transcriptomic signature, alongside CNS-resident inflammation, progressive demyelination, and motor disability. Mechanistically, C-terminal TAF1 interacts with MS-linked factors that cooperate to regulate RNAPII pausing, particularly affecting oligodendroglial myelination genes. These findings uncover a previously unrecognized transcriptional mechanism underlying MS progression and establish a tractable in vivo model for therapeutic development.

neuroscience↗

bioRxiv2023

Gliogenesis from the subventricular zone modulates the extracellular matrix at the glial scar after brain ischemia

Activation of the subventricular zone (SVZ) following cerebral ischemia is one of the brains early responses to counteract neuron loss and minimize tissue damage. Impaired brain regions communicate with the SVZ through various chemotactic signals that promote cell migration and differentiation, primarily involving neural stem cells (NSC), neuroblasts, or glioblasts. However, the activation of gliogenesis and the role of newly formed astrocytes in the post-ischemic scenario remain subjects of debate. We have previously demonstrated that adenosine release after brain ischemia prompts the SVZ to generate new astrocytes. Here, we used transient brain ischemia in mice to identify the cellular origin of these astrocytes within the SVZ neurogenic niche and to investigate their role in the pathological process. By combining immunofluorescence, BrdU-tracing, and genetic cell labeling, we tracked the migration of newborn astrocytes, positive for the proteoglycan marker Thbs4, from the dorsal and medial SVZ to the perilesional barrier surrounding the ischemic core, known as the "glial scar". We found that these Thbs4-positive astrocytes modulate the dense extracellular matrix at the lesion border by both synthesizing and degrading hyaluronan. We also show that while the accumulation of hyaluronan at the lesion site is sufficient to recruit newborn astrocytes, its degradation at the SVZ correlates with gliogenesis. These findings suggest that newborn astrocytes could be a promising pharmacological target for modulating the glial scar after brain ischemia and facilitate tissue regeneration.

neuroscience↗