| First Author | Chen G | Year | 2021 |
| Journal | Sci Adv | Volume | 7 |
| Issue | 16 | PubMed ID | 33863723 |
| Mgi Jnum | J:358337 | Mgi Id | MGI:6809704 |
| Doi | 10.1126/sciadv.abe4499 | Citation | Chen G, et al. (2021) Netrin-1 receptor UNC5C cleavage by active delta-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies. Sci Adv 7(16) |
| abstractText | Netrin-1, a family member of laminin-related secreted proteins, mediates axon guidance and cell migration during neural development. T835M mutation in netrin receptor UNC5C predisposes to the late-onset Alzheimer's disease (AD) and increases neuronal cell death. However, it remains unclear how this receptor is molecularly regulated in AD. Here, we show that delta-secretase selectively cleaves UNC5C and escalates its proapoptotic activity, facilitating neurodegeneration in AD. Netrin deficiency activates delta-secretase that specifically cuts UNC5C at N467 and N547 residues and enhances subsequent caspase-3 activation, additively augmenting neuronal cell death. Blockade of delta-secretase cleavage of UNC5C diminishes T835M mutant's proapoptotic activity. Viral expression of delta-secretase-truncated UNC5C fragments into APP/PS1 mice strongly accelerates AD pathologies, impairing learning and memory. Conversely, deletion of UNC5C from netrin-1-depleted mice attenuates AD pathologies and rescues cognitive disorders. Hence, delta-secretase truncates UNC5C and elevates its neurotoxicity, contributing to AD pathogenesis. |
