| Gene |
UNC5C |
| UniProt |
Q9NUP9 |
| PDB |
6UWG |
| Molecular Weight |
102 kDa |
| Subcellular Localization |
Plasma membrane, axon guidance receptors |
| Protein Family |
Unc-5 netrin receptor family |
UNC5C (Unc-5 Netrin Receptor C) is a member of the UNC-5 family of netrin receptors that play crucial roles in axon guidance and cell migration during development. In the adult nervous system, UNC5C continues to function in synaptic plasticity and has been implicated in Alzheimer's disease pathogenesis. Genetic variants in UNC5C have been associated with increased AD risk in genome-wide studies.
UNC5C is a transmembrane receptor composed of:
- Extracellular domain: Contains two immunoglobulin-like (Ig) domains and two thrombospondin type I (TSR) repeats that mediate netrin binding
- Transmembrane domain: Single-pass transmembrane helix
- Intracellular domain: Contains a Death Domain (DD) and a ZU5 domain that mediate downstream signaling
During development, UNC5C receptors mediate repulsion from netrin-1 gradients, guiding axons to their proper targets:
- Axon guidance: Repels axons from the midline in the developing spinal cord
- Cell migration: Regulates neuronal migration during corticogenesis
- Circuit formation: Helps establish proper neural connectivity
In the adult brain, UNC5C participates in:
- Synaptic plasticity: Modulates dendritic spine morphology and function
- Axon maintenance: Maintains axonal integrity in mature neurons
- Response to injury: Involved in regenerative responses after neuronal injury
Genome-wide association studies (GWAS) have identified UNC5C variants associated with AD risk:
- Certain UNC5C polymorphisms increase AD susceptibility
- The mechanism involves altered neuronal connectivity and synaptic function
UNC5C contributes to AD through multiple mechanisms:
- Synaptic dysfunction: Alters synaptic plasticity and dendritic spine morphology
- Axonal degeneration: Impairs axonal maintenance and repair
- Neuronal vulnerability: Increases susceptibility to amyloid toxicity
UNC5C interacts with amyloid pathways:
- Amyloid-beta affects UNC5C expression and localization
- UNC5C deficiency exacerbates amyloid-induced synaptic deficits
- Netrin-1, the UNC5C ligand, is altered in AD brains
UNC5C represents a potential therapeutic target:
- Netrin-1 mimetics: Could enhance neuroprotective signaling
- Small molecule agonists: Being developed to enhance UNC5C function
- Gene therapy: Approaches to restore UNC5C expression
- UNC5C Gene
- Netrin-1 Signaling
- Axon Guidance in Neurodegeneration
- Synaptic Dysfunction in AD