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Characterization of synaptic and epigenetic alterations in the context of the astrocytic pathology in progressive Supranuclear Palsy and Corticobasal Degeneration
Get PDFNeurodegenerative 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
Follikuläre Lymphome – Therapierealität an der Medizinischen Klinik III im Klinikum der Universität München (LMU Klinikum)
Get PDFInteraktionen zytotoxischer T-Zellen mit myeloiden Zellen als Determinanten antigenspezifischer Immunantworten bei HIV-Infektionen und Malignomen
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Nutrient-dependent regulation of histone homeostasis in Saccharomyces cerevisiae
Get PDFRegulation of cellular protein homeostasis in response to environmental challenges such as nutrient availability is essential for maintaining cell function and viability. The surrounding nutrients strongly influence cell growth and biosynthetic capacity, dictating, among others, cellular growth rate, cell size and cell cycle progression. Ensuring protein homeostasis therefore requires cells to tightly control RNA and protein concentrations, even when cell growth and the cell cycle are significantly modulated by nutrient conditions. This poses a challenge, especially for genes whose expression is highly regulated throughout the cell cycle. A comprehensive picture of how cells achieve nutrient-dependent homeostasis of periodically expressed genes remains elusive.
In this work, I study histone biogenesis in the model organism Saccharomyces cerevisiae to investigate how cells produce the appropriate amount of histones in different nutrient environments. Histones constitute an ideal model to understand differential regulation of cell cycle-regulated proteins, as their synthesis is strongly coordinated with the DNA replication during S-phase. Moreover, as building blocks of chromatin, histones are produced in proportion to the genome content, which requires accurate control of histone concentrations. To understand the regulatory processes underlying nutrient-dependent histone homeostasis, I perform population and single-cell analyses of histone expression at the protein and mRNA level.
Using western blots, flow cytometry and live-cell imaging, I first show that cells maintain constant amounts of the core histone H2B in rich and poor nutrients, independent of changes in cell growth and cell cycle. As a result, H2B concentrations increase in poor growth media, due to the smaller cell volumes. Surprisingly, however, I find that histone mRNA concentrations are downregulated in poor compared to rich nutrients. smFISH analysis of histone promoter-driven mCitrine expression further reveals that the promoter can confer this nutrient-dependent transcript regulation, which depends on regulatory elements within the promoter, as well as the transcriptional activator Spt10. Furthermore, my results suggest that cells in poor growth media are more sensitive to excess histone accumulation than cells in rich growth media. By keeping histone transcript levels low, they may therefore minimize the risk of histone overexpression. Finally, I propose that cells compensate for the differentially regulated histone transcript concentrations by modulating the relative translation efficiency according to the nutrient conditions. Thereby, they can finely tune histone protein abundance across nutrients, while preventing high histone accumulation in poor growth media. Overall, I show that the decoupling of mRNA and protein concentrations enables nutrient-dependent histone homeostasis despite changes in cell growth and cell cycle phases. This work could lay the foundation for a deeper understanding of the differential regulation of cell cycle-regulated genes across changing nutrient environments
Analyse sozialer und ökonomischer Determinanten der Wohnungsnachfrage und des Heizenergiebedarfs
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