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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.<\/jats:p>","DOI":"10.1038\/s41598-025-32069-9","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T12:26:16Z","timestamp":1765455976000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Regulation of glypican 6-mediated Wnt activation maintains TDP-43 nuclear localization in neurons"],"prefix":"10.1038","volume":"16","author":[{"given":"Nan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanthini","family":"Sockanathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"32069_CR1","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.molmed.2013.11.003","volume":"20","author":"L Vanden Broeck","year":"2014","unstructured":"Vanden Broeck, L., Callaerts, P. & Dermaut, B. 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