Characterization of synaptic and epigenetic alterations in the context of the astrocytic pathology in progressive Supranuclear Palsy and Corticobasal Degeneration

Briel, Nils (2024): Characterization of synaptic and epigenetic alterations in the context of the astrocytic pathology in progressive Supranuclear Palsy and Corticobasal Degeneration. Dissertation, LMU München: Medizinische Fakultät

Abstract

Neurodegenerative diseases are characterized by the presence of aggregated pathological proteins associated with cell degeneration in vulnerable brain areas. Research efforts have been undertaken to reveal the underlying molecular mechanisms of neurodegeneration and astrogliopathies. The latter are diseases with significant contributions by astrocytes such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). However, their molecular pathogenesis remains insuf-ficiently understood. This work is dedicated to the investigation of astrocytes in PSP and CBD. In the first project, immu-nofluorescence synapse labelling was applied with automated puncta quantification in postmortem brain tissue of a selected PSP/CBD cohort. To gather a deeper molecular understanding, we then generated and analyzed a single-nucleus chromatin accessibility dataset from postmortem cortical tissue of a separate tauopathy cohort. The overarching research aims were to identify contributions of the astrocytic Tau inclusion pathology to alterations in synaptic structure and epigenetic net-works. The findings suggest that a general synapse loss in PSP is not associated with astrocytic Tau inclu-sions, while in CBD synapse density is negatively correlated with the typical astrocytic Tau patholo-gy. Furthermore, synapse alterations within astrocytic spatial domains reflect the distribution of proximal versus peripheral Tau aggregates in PSP and CBD, respectively. This underpins the im-portance of these cells in maintaining synaptic contacts, which are considered as correlates of cog-nitive function. We integrated our generated chromatin accessibility data with publicly available ge-netic risk variant and bulkRNA-sequencing data to identify pathways and transcription factors (TFs) that are linked to Tau pathology. Genetic risk variants associated with PSP and FTD diagnoses were exclusively enriched in astrocytic accessible chromatin regions. Protein degradation systems were differentially deregulated across neuroglial populations in both tauopathies, with highly increased ubiquitin proteasome system and autophagy in PSP microglia and trending autophagy upregulation in CBD astrocytes. In pseudotime analyses of astrocytic nuclei, immediate early response (IER) and homeostasis transcription factors (TFs) (e.g., JUN, FOS, TFEB) were increased at the expense of early differentiation candidates (e.g., LHX9, EMX1/2). Modeling of TF representations emphasized the relevance of IER-related TFs. Furthermore, in combination with an external dataset, we defined astrocytic Tau TF signatures comprising JUN/FOS, NFIA, SP1, and TFEB, among others. At the protein level, the JUN/FOS target and upstream regulator MAP3K8, and TFEB’s effector lysosomal protease CTSD essentially showed concordant deregulation. These results establish a strong association of disease-relevant molecular and synaptic changes with astrocytes and demonstrate that genetic risk for disease manifestation is tightly linked to as-trocytic chromatin accessibility profiles. We also identified marked differences related to protein homeostasis and TF networks between both diseases. Altogether, these findings emphasize the interactions between astrocytes and Tau as an important subject of prospective research.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 25. Januar 2024
• 1. Bericht­erstatter:in: Herms, Jochen