| 2005 |
GDE2 (GDPD5) is a six-transmembrane protein that is necessary and sufficient to drive spinal motor neuron differentiation in vivo; a single amino acid mutation in the extracellular catalytic domain abolishes protein function, demonstrating that glycerophosphodiester metabolism in the extracellular domain is required. |
In vivo gain- and loss-of-function experiments in chick and mouse spinal cord; active-site mutagenesis |
Science |
High |
16195461
|
| 2008 |
GDPD5 functions as a glycerophosphocholine phosphodiesterase (GPC-PDE) that degrades GPC to glycerol-3-phosphate and choline; recombinant GDPD5 immunoprecipitated from HEK293 cells degrades GPC in vitro, and siRNA knockdown increases cellular GPC levels, while overexpression decreases GPC. |
In vitro enzymatic assay with immunoprecipitated recombinant protein; siRNA knockdown; overexpression in IMCD-3 cells |
Proceedings of the National Academy of Sciences of the United States of America |
High |
18667693
|
| 2009 |
Peroxiredoxin 1 (Prdx1) interacts with GDE2 and activates it by reducing an intramolecular disulfide bond bridging the intracellular N- and C-terminal domains; GDE2 variants incapable of disulfide bond formation become constitutively active and independent of Prdx1. |
Co-immunoprecipitation; disulfide bond mutagenesis; loss-of-function genetics (Prdx1 KO mice); motor neuron differentiation assays |
Cell |
High |
19766572
|
| 2011 |
GDE2, expressed in postmitotic motor neurons, induces motor neuron generation through a non-cell-autonomous mechanism: its extracellular glycerophosphodiester phosphodiesterase activity inhibits Notch signaling in adjacent motor neuron progenitors, controlling subtype-specific motor neuron production. |
Gde2 knockout mouse analysis; histology; epistasis with Notch pathway |
Neuron |
High |
21943603
|
| 2013 |
GDE2 cleaves GPI anchors (unlike classical GDPDs which cleave glycerophosphodiesters) and uses this GPI-anchor cleavage activity to release RECK from the membrane; RECK release disinhibits ADAM protease-dependent shedding of Delta-like 1 (Dll1), leading to Notch inactivation and neurogenesis. |
GPI-anchor cleavage assay; biochemical fractionation; epistasis with RECK, ADAM proteases, and Dll1-Notch pathway; active-site mutagenesis |
Science |
High |
23329048
|
| 2013 |
High NaCl and high urea inhibit GDPD5 GPC-PDE activity via at least three post-translational modifications: (i) formation of a disulfide bond between C25 and C571 (promoted by ROS); (ii) dephosphorylation of T587 (constitutively phosphorylated, and dephosphorylation reduces activity); (iii) an additional modification mediated by CDK1. These PTMs collectively increase cellular GPC levels. |
Site-directed mutagenesis (C25S/C571S, T587A); CDK1 pharmacological inhibition; antioxidant treatment; in vitro GPC-PDE activity assays; mass spectrometry of PTMs |
Proceedings of the National Academy of Sciences of the United States of America |
High |
23589856
|
| 2015 |
Prdx4, an ER-resident H2O2-metabolizing enzyme, oxidizes two cysteine residues within the GDE2 enzymatic domain via Prdx4 dimers generated by H2O2 metabolism; this oxidation blocks GDE2 trafficking to the plasma membrane and prevents its neurogenic function. |
Prdx4 knockout mouse; biochemical oxidation assays; subcellular fractionation/trafficking assays; motor neuron differentiation readouts; cysteine mutagenesis |
Nature communications |
High |
25943695
|
| 2010 |
GDP-bound Gαi2 interacts with GDE2 in motor neuron progenitors; disruption of the GDE2/Gαi2 complex in vivo causes motor neuron deficits analogous to Gαi2 ablation, indicating Gαi2 regulates motor neuron differentiation in part through this interaction. |
Co-immunoprecipitation; in vivo dominant-negative and knockdown in chick spinal cord; Gαi2 KO mice; motor neuron counting |
Developmental biology |
Medium |
20197066
|
| 2012 |
Gde2 controls the timing of cortical progenitor cell-cycle exit; in Gde2 knockout mice, cortical progenitors fail to exit the cell cycle on time, correlating with elevated Notch signaling, causing deficits in deep-layer neurons and excess superficial-layer neurons. |
Gde2 knockout mouse; BrdU birthdating; immunohistochemistry; Notch signaling assays |
Development |
Medium |
22951639
|
| 2016 |
GDE2 induces neuroblastoma cell differentiation and suppresses cell motility by cleaving (in cis) the GPI-anchored glypican-6 (GPC6) and releasing it from the membrane; a single point mutation in the ectodomain abolishing catalytic activity also abolishes GDE2 differentiation function, and GDE2 alters the Rac-RhoA activity balance. |
GPI-anchor cleavage assay; active-site mutagenesis; GPC6 surface-release experiments; Rac/RhoA activity assays; neuroblastoma cell differentiation assays |
Cancer cell |
High |
27693046
|
| 2017 |
Adult mice lacking GDE2 develop progressive neuronal degeneration; conditional deletion of GDE2 after embryonic neurogenesis still causes degeneration, showing the survival function is distinct from the differentiation function. Unbiased screening identifies impaired processing of GPI-anchored Glypican 4 and 6 as molecular correlates. |
Constitutive and conditional (postnatal) Gde2 KO mouse; histology; electrophysiology; behavioral assays; proteomics screen for GPI-anchored substrates |
Molecular neurodegeneration |
High |
28103900
|
| 2020 |
GDE2 expressed in neurons activates canonical Wnt signaling, leading to secretion of soluble factors (including phosphacan) that promote oligodendrocyte maturation; Gde2KO neurons show reduced Wnt signaling and genetic activation of Wnt in Gde2KO neurons rescues oligodendrocyte maturation both in vivo and in vitro. |
Global and neuron-specific Gde2 KO mice; conditioned medium experiments; Wnt signaling reporter assays; genetic rescue with constitutively active Wnt components; phosphacan quantification |
Cell reports |
High |
32375055
|
| 2020 |
GDE2 expressed in oligodendrocytes cell-autonomously slows the pace of oligodendrocyte maturation; oligodendrocyte-specific Gde2 KO mice show accelerated oligodendrocyte maturation and increased myelination, phenocopied in purified primary oligodendrocyte cultures. |
Oligodendrocyte-specific Cre-lox KO (O-Gde2KO); immunohistochemistry for myelin proteins; primary oligodendrocyte cultures |
Developmental dynamics |
Medium |
33095500
|
| 2020 |
GDE2 trafficking is regulated by C-terminal tail sequences that control constitutive endocytosis and recycling; a C-terminal leucine residue in a unique motif is essential for GDE2 internalization, and a truncation mutant with aberrant recycling fails to cleave GPI-anchored GPC6 and is non-functional, whereas a consecutive deletion causing surface retention gains function. |
Live-cell imaging; FRAP; C-terminal deletion/truncation mutagenesis; GPC6 cleavage assay; neuronal differentiation assays |
Journal of cell science |
High |
31932507
|
| 2021 |
GDE2 stimulates ADAM10 α-secretase cleavage of amyloid precursor protein (APP) by shedding and inactivating the GPI-anchored RECK protein, a known ADAM10 inhibitor; genetic ablation of GDE2 elevates membrane-bound RECK, reduces sAPPα generation, increases Aβ, and causes synaptic protein loss. In Alzheimer's disease tissue, GDE2 is abnormally sequestered intracellularly and membrane RECK is elevated. |
Gde2 KO mouse; RECK genetic reduction rescue experiments; APP processing biochemical assays (sAPPα, Aβ measurements); human AD postmortem tissue analysis; synaptic protein quantification |
Science translational medicine |
High |
33731436
|
| 2022 |
In ALS patient post-mortem tissue, total GDE2 protein levels are normal but membrane GDE2 is substantially reduced, with GDE2 aberrantly accumulating in intracellular compartments of motor cortex neurons; haplogenetic reduction of GDE2 exacerbates motor neuron degeneration in SOD1G93A mice; tandem-mass-tag MS reveals reduced GPI-anchored protein release into CSF of ALS patients. |
Human ALS postmortem tissue immunohistochemistry and fractionation; SOD1G93A mouse genetic interaction; tandem-mass-tag mass spectrometry of CSF |
Acta neuropathologica communications |
Medium |
35550203
|
| 2024 |
GDE2 regulates the number and molecular composition of small extracellular vesicles (sEVs) released from neuronal cell surfaces via its GPI-anchor cleavage activity; proteomic profiling identifies at least two distinct GDE2-dependent sEV populations—one containing GDE2 itself and one harboring CD9 and BSG—enriched in cytoskeletal, actin-remodeling, synaptic, and redox proteins. |
Gde2 KO neurons; sEV isolation and quantification; proteomic profiling (mass spectrometry); functional GPI-cleavage activity assays |
Cells |
Medium |
39272985
|
| 2024 |
PRKDC recruits and binds GDE2; this interaction enhances GNAS protein stability, which activates AKT phosphorylation and confers doxorubicin resistance in osteosarcoma. |
CRISPR kinome screen; co-immunoprecipitation; protein stability assays; phospho-AKT measurements; xenograft and organoid rescue experiments |
Cancer research |
Medium |
38900943
|
| 2025 |
GDE2 regulates hippocampal CA1 synaptic morphology and function; Gde2KO mice show increased dendritic complexity, excess mushroom spines, increased mEPSC frequency, impaired paired-pulse facilitation, and disrupted NMDAR-mediated LTD. Mechanistically, abnormal activation of the PI3K-AKT-GSK3 signaling pathway in Gde2KO hippocampus underlies LTD impairment, and PI3K inhibition restores LTD to WT levels. |
Gde2 KO mouse; electrophysiology (mEPSC, PPF, LTD); dendritic morphology analysis; PI3K-AKT-GSK3 pathway biochemistry; pharmacological PI3K inhibition rescue |
eNeuro |
Medium |
40634123
|
| 2025 |
GDE2 inhibits excessive neuronal Wnt activation by regulating the surface expression of GPI-anchored Glypican 6 (GPC6); elevated GPC6 surface expression potentiates neuronal Wnt activation, causing nuclear pore complex disruption, altered Ran-dependent nucleocytoplasmic trafficking, and TDP-43 mislocalization; genetic reduction of GPC6 in Gde2KO mice rescues all these defects. |
In vivo mouse genetics (Gde2KO, GPC6 genetic reduction rescue); nuclear pore complex integrity assays; Ran-NCT assays; TDP-43 localization immunohistochemistry; Wnt signaling reporters |
bioRxivpreprint |
Medium |
bio_10.1101_2025.09.24.678385
|