TAR-DNA binding protein 43 (TDP-43) is a nuclear protein that has been implicated in several neurodegenerative diseases, including Frontotemporal Lobar Degeneration (FTLD-TDP), Amyotrophic Lateral Sclerosis (ALS), and Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), among other age-related dementias. The presence of TDP-43 aggregates in the cytoplasm of neurons and glial cells, particularly in oligodendrocytes (OLs), is the neuropathological hallmark of FTLD-TDP, ALS, and LATE-NC. Similar to other misfolded proteins (i.e., α-synuclein, β-amyloid and Tau), the transmission of pathogenic TDP-43 species between cells could contribute to disease progression in neurodegenerative diseases. Our group has recently shown that pathological TDP-43 derived from FTLD-TDP brain extracts can act as pathogenic seeds and induce the formation of de novo TDP-43 pathology when injected in the brain of TDP-43 transgenic mice, and to a lesser extent in wild-type mice (WT). Under this paradigm, TDP-43 pathology spreads throughout the brain in a regional and time-dependent manner. Interestingly, as found in diseased human brains, TDP-43 pathology is present in neurons and OLs. Despite several studies indicating that TDP-43 pathology in OLs is a common feature of various neurodegenerative diseases, including AD and FTLD-TDP, the consequences of TDP-43 pathology in OLs remains unknown. The present research project aims to develop in vitro models to study the pathophysiological consequences of TDP-43 pathology in OLs and evaluate the role of OLs in facilitating the spread of TDP-43 pathogenic species between glial and neuronal cells.