Tpr regulates nuclear pore complex numbers in hippocampal neural stem cells in Alzheimer’s disease

Abstract: Nuclear pore complexes are highly dynamic macromolecular protein structures that facilitate the molecular exchange across the nuclear envelope. Aberrant nuclear pore complex functioning is implicated in neurodegeneration. However, the functional role of Tpr in neural stem / progenitor cell (NSPC) subpopulations in the hippocampus in CNS disease is not understood. We found that the localization of Tpr changes upon post translational modification in proliferating NSPCs. Using high-end microscopy techniques, like super resolution microscopy and electron microscopy studies, we found phospho-Tpr localized to the nucleus of dividing DCX+ neuroblasts, while Tpr is localized to the nuclear membrane. Apart from the localization difference, we observed an increased expression of Tpr through NSPC differentiation, contradicting the regular expression of FG-Nups. Furthermore, Tpr expression increases from immature NSPCs of the dentate gyrus to mature neurons in the granule cell layer of the mouse hippocampus. In a mouse model of neurodegeneration, the 5xFAD mouse model of AD, Tpr expression increased prior to the disease pathology, preceding an increase in neurogenesis, suggesting that Tpr might be involved in NSPC fate regulation. We developed a customized 3D nuclear envelope analysis by masking the inner and outer nuclear envelope components for high throughput analysis of nuclear pore complex (NPC) remodeling in the disease paradigm and identified a reduction of NPC numbers in DCX+ immature neurons of the hippocampus in the 5xFAD mice. Mass spectrometry and GO term analysis revealed the Tpr interactome, potentially regulating chromatin reorganization. We found that the P-Tpr interaction partners are unique and do not coincide with Tpr interaction partners. Specifically, P-Tpr interacts with CDK1 which is a critical cell cycle regulator. We predict that posttranslational modification of Tpr alters its localization and interactome, regulating cell cycle progression and division of NSPCs via interaction with chromatin remodeling proteins

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2023

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Malik, Subash C.
• Contributor: Schachtrup, Christian ; Schachtrup, Christian ; Claßen, Anne-Kathrin ; Albert-Ludwigs-Universität Freiburg. Institut für Anatomie und Zellbiologie ; Albert-Ludwigs-Universität Freiburg. Abteilung für Molekulare Embryologie ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Further information

• DOI: 10.6094/UNIFR/233846
• URN: urn:nbn:de:bsz:25-freidok-2338468
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:55 PM CET