Regulation of Glypican 6-mediated Wnt activation maintains TDP-43 nuclear localization in neurons

Abnormalities in TDP-43 (Transactive response DNA-binding protein 43kDa) localization and function span multiple neurodegenerative diseases and are implicated in driving neuronal degeneration and loss. Nuclear pore complex (NPC) abnormalities and disrupted nucleocytoplasmic trafficking (NCT) contribute to TDP-43 mislocalization, but how these cellular changes are initiated in disease is unclear. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a surface glycosylphosphatidylinositol (GPI)-anchor cleaving enzyme that encodes a physiological pathway that ensures NPC integrity, appropriate NCT, and nuclear TDP-43 expression and function in adult neurons by negatively regulating canonical Wnt signaling. Notably, studies of human postmortem tissue and patient-derived neuronal models suggest that the failure of GDE2-dependent regulation of Wnt contributes to TDP-43 abnormalities in disease. Here we show that GDE2 inhibits persistent neuronal Wnt activation by regulating the surface expression of the GPI-anchored protein, Glypican-(GPC)6. Excessive GPC6 surface expression potentiates neuronal Wnt activation in vivo, resulting in NPC disruption, alterations in Ran-dependent NCT, and TDP-43 mislocalization, while genetic reduction of GPC6 in mice lacking GDE2 rescues these cellular abnormalities. Thus, GDE2, GPC6, and the canonical Wnt pathway form a physiologically important signaling axis important for NPC integrity, appropriate NCT, and TDP-43 nuclear function in neurons that, when disrupted, may underlie associated neuropathologies in disease.