Project Details
Projekt
Driving forces and pathological consequences of aberrant TDP-43 phase transitions in neurons and glial cells
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 419139133
Aberrant liquid liquid phase separation (LLPS) and liquid-to-solid phase transitions are thought to underlie the formation of cytosolic aggregates containing the RNA-binding protein TDP-43 (TAR DNA binding protein of 43 kDa) in neurodegenerative disorders and after traumatic brain injuries. Aggregation of TDP-43 in neurons and glial cells is thought to contribute to neurodegeneration through TDP-43 loss-of-function and/or gain-of-function mechanisms. Our preliminary data indicate that aberrant phase transitions of TDP-43 in microglia upon brain injury in zebrafish lead to microglial activation and promote their accumulation at injury sites. We furthermore found that TDP-43 condensation in microglia is promoted by loss of Progranulin (PGRN) and that PGRN suppresses TDP-43 condensation in vitro. The loss of PGRN function and prolonged TDP-43 driven microglial activation impairs brain regeneration in zebrafish.This proposal aims at deciphering the molecular driving forces of TDP-43 phase transitions and how disease-linked mutations and the disease-linked PGRN protein regulate TDP-43 phase transitions in neuronal and glial cells. To this end, we will study how rationally designed and disease-linked mutations in the TDP-43 sequence affect TDP-43 phase separation behavior in vitro. Taking advantage of TDP-43 mutants with altered phase separation behavior, we will investigate how aberrant TDP-43 phase separation affects the dynamic properties of TDP-43 condensates in neuronal cell lines and mixed glial cultures containing microglia. Moreover, we will decipher how aberrant TDP-43 phase separation affects TDP-43 uptake into neuronal and glial cells as well as microglial functions and activation state. Finally, we aim to understand how PGRN interacts with TDP-43 to suppress TDP-43 condensation in vitro and in vivo. We expect that a molecular understanding of TDP-43 phase transitions and the direct comparison of TDP-43 phase transitions in different neural cell types will enhance our understanding of the pathological relevance of aberrant phase transitions and will identify how they alter the physiological functions and properties of disease-relevant cell types.
DFG Programme
Priority Programmes
