Abberant neuronal Wnt activation causes defective TDP43 localization

Conserved neuropathologies across multiple neurodegenerative diseases have identified shared causal pathways for neurodegeneration. One pathway involves the RNA-binding protein TDP-43, whose nuclear exclusion and cytoplasmic accumulation are established drivers of neurodegeneration. TDP-43 mislocalization is attributed to defective nucleocytoplasmic transport (NCT), but the underlying mechanisms are unclear. The vertebrate-specific six-transmembrane enzyme, Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5), cleaves the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. Here, we show that loss of GDE2 leads to aberrant sustained activation of canonical Wnt signaling in adult neurons, which is sufficient to cause NCT and nuclear pore abnormalities and the nuclear exclusion of TDP-43. GDE2 disruption coincides with TDP-43 nuclear exclusion in postmortem tissue from patients with Amyotrophic Lateral Sclerosis (ALS), and neuronal Wnt signaling is erroneously activated in Drosophila and induced human spinal neuronal (iSN) models of ALS. Wnt knockdown in Drosophila ALS models mitigates cell death, while pharmacological inhibition of Wnt activation in iSNs from ALS patients rescues mRNA levels of known TDP-43 splicing targets. Our study identifies GDE2 as a critical regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as a previously unappreciated mechanism contributing to NCT and TDP-43 abnormalities in disease.