| UniProt ID | [O75487](https://www.uniprot.org/uniprotkb/O75487) |
| Gene | [GPC4](/genes/gpc4) |
| MW | ~58 kDa (core) |
| Location | Neuronal surface, synaptic membranes |
| Structure | GPI-anchored HSPG |
Glypican-4 Protein is a protein that ### Synaptic Development and Plasticity. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Glypican-4 (GPC4, also known as K-glypican) is a GPI-anchored heparan sulfate proteoglycan (HSPG) with critical roles in neurodevelopment, synaptic maturation, and neural circuit formation. While less studied than Glypican-1 in the context of neurodegeneration, emerging evidence highlights its importance in synapse organization, astrocyte-neuron communication, and potential roles in neurodegenerative disease.[1]
Glypican-4 shares the conserved glypican family architecture:[2]
The protein folds into a compact globular structure with heparan sulfate chains extending from the C-terminal region.
Glypican-4 plays essential roles in synapse formation:[3]
GPC4 is a key mediator of astrocyte-secreted synaptogenic signals:[4]
During brain development:[5]
While direct links to neurodegeneration are still emerging, GPC4's synaptic roles suggest potential involvement:[6]
| Neurodegenerative Feature | Potential GPC4 Role |
|---|---|
| Synaptic loss | Failed maintenance of mature synapses |
| Excitotoxicity | Altered excitatory/inhibitory balance |
| Astrocyte dysfunction | Impaired astrocyte-neuron communication |
| Circuit disruption | Aberrant synaptic connectivity |
Preliminary evidence suggests GPC4 may be relevant to Alzheimer's disease:[7]
GPC4 has been linked to neurodevelopmental conditions with potential neurodegenerative components:[8]
Like other HSPGs, Glypican-4 can interact with Aβ:[9]
| Strategy | Application | Status |
|---|---|---|
| Recombinant GPC4 | Synapse repair | Preclinical |
| GPC4 antibodies | Modulate synaptogenesis | Research |
| HS mimetics | Block pathological protein binding | Preclinical |
| Gene therapy | Restore GPC4 function | Conceptual |
| Interacting Partner | Type | Function |
|---|---|---|
| LRRTM4 | Physiological | Synaptogenesis |
| Neurexins | Physiological | Trans-synaptic adhesion |
| Glutamate receptors | Physiological | Synaptic function |
| Amyloid-β | Pathological | Potential aggregation |
| FGF family | Physiological | Growth factor co-receptor |
Filmus J, et al. Glypicans. Genome Biol. 2008;9(5):224. doi:. 10.1186/gb-2008-9-5-224. 2008. ↩︎
Svensson G, et al. Crystal structure of the human glypican-1 core protein. J Biol Chem. 2015;290(48):28959-28971. doi:. 10.1074/jbc.M115.680323. 2015. ↩︎
Allen NJ, et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature. 2012;486(7403):410-414. doi:. 10.1038/nature11059. 2012. ↩︎
Farhy-Tselnicker I, et al. Astrocytes regulate the development and maturation of excitatory synapses through secretion of glypicans. Cell Rep. 2017;20(6):1313-1325. doi:. 10.1016/j.celrep.2017.07.041. 2017. ↩︎
Niu H, et al. GPC4 regulates cerebral cortical development by promoting radial glial scaffold formation. J Cell Sci. 2019;132(14):jcs232950. doi:. 10.1242/jcs.232950. 2019. ↩︎
Chung WS, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504(7480):394-400. doi:. 10.1038/nature12776. 2013. ↩︎
Perez SE, et al. Altered hematopoietic and immune system development in the absence of glypican-4. FASEB J. 2018;32(10):5481-5493. doi:. 10.1096/fj.201701223RRR. 2018. ↩︎
Doan RN, et al. Mutations in glypican genes and risk for autism spectrum disorders. J Neurodev Disord. 2016;8:34. doi:. 10.1186/s11689-016-9168-2. 2016. ↩︎
Holmes BB, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci USA. 2013;110(33):E3138-3147. doi:. 10.1073/pnas.1301440110. 2013. ↩︎