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

## TL;DR

This study shows how a signaling pathway involving GDE2 and GPC6 regulates TDP-43 localization in neurons, and disruptions in this pathway may lead to neurodegenerative diseases.

## Contribution

The study identifies a novel GDE2-GPC6-Wnt signaling axis that regulates nuclear pore integrity and TDP-43 localization in neurons.

## Key findings

- GDE2 inhibits Wnt activation by regulating GPC6 surface expression.
- Excessive GPC6 causes nuclear pore disruption and TDP-43 mislocalization.
- Reducing GPC6 rescues cellular abnormalities in GDE2-deficient mice.

## Abstract

Abnormalities in TDP-43 (Transactive response DNA-binding protein 43 kDa) 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.

The online version contains supplementary material available at 10.1038/s41598-025-32069-9.