The role of OPC-microglia interactions in TDP-43-related neurodegeneration

PROJECT SUMMARY TAR DNA-binding protein-43 (TDP-43) aggregation is seen in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases present a significant burden to patients and caregivers, with little promising intervention to date. Interactions between oligodendrocyte precursor cells (OPCs) and microglia are increasingly recognized to play a role in disease states. OPCs are able to differentiate into oligodendrocytes, the primary myelin-forming cells of the central nervous system (CNS). However, they are also involved in modulating activity of immune cells such as microglia, the principal immune cells of the CNS. In models of neuroinflammation and neurodegeneration, OPCs play a neuroprotective role in attenuating detrimental microglial proliferation. Understanding the mechanistic details of this OPC-mediated neuroprotection has therapeutic implications. The objective of the proposed research is to determine the mechanism underlying OPC-microglia interactions in TDP-43-related neurodegeneration and outline the functional significance in terms of disease outcome. Our preliminary data in the rNLS8 mouse model of inducible TDP-43 expression suggests that OPC-microglia interactions significantly increase during disease. Performing predictive ligand-receptor analysis of transcriptomic data from human ALS patients highlights microglial secreted phosphoprotein 1 (SPP1) signaling to OPC integrin receptors as a likely mechanism. We hypothesize that increased OPC-microglia interactions occur through enhanced SPP1 signaling during TDP-43-related neurodegeneration and serve a protective role by reducing microglial numbers and neuroinflammation. To accomplish our objectives, we will use transgenic and viral mouse models of TDP-43-related neurodegeneration. We will first address whether SPP1 signaling to OPC integrin receptors mediates this interaction through immunohistochemical (IHC) staining and use of an SPP1 genetic knockout mouse model. To investigate real-time dynamics and ultrastructure of this interaction, we will perform in vivo two-photon imaging and serial block-face scanning electron microscopy. We next address the effect of OPC-microglia interactions on disease progression through a pharmacogenetic OPC ablation mouse model. Following ablation, we will measure readouts of neuroinflammation, neuropathology, and motor behavior function. Finally, we will confirm the translational relevance of our findings by performing IHC staining to assess OPC-microglia interactions in human ALS and FTD tissue. Successfully completing these aims will unveil a critical regulatory axis of neuroinflammation in TDP-43-related neurodegeneration, providing a foundation for targeted therapeutic interventions.