Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies

  • Sci Adv. 2021 Apr 16;7(16):eabe4499. doi: 10.1126/sciadv.abe4499.
Guiqin Chen  1  2 ,  Seong Su Kang  1 ,  Zhihao Wang  1 ,  Eun Hee Ahn  1 ,  Yiyuan Xia  1 ,  Xia Liu  1 ,  Ivette M Sandoval  3 ,  Fredric P Manfredsson  3 ,  Zhaohui Zhang  4 ,  Keqiang Ye  5
Affiliations
  • 1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
  • 3. Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, USA.
  • 4. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China. [email protected] [email protected].
  • 5. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. [email protected] [email protected].
PMID: 33863723 DOI: 10.1126/sciadv.abe4499
Abstract

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 δ-secretase selectively cleaves UNC5C and escalates its proapoptotic activity, facilitating neurodegeneration in AD. Netrin deficiency activates δ-secretase that specifically cuts UNC5C at N467 and N547 residues and enhances subsequent Caspase-3 activation, additively augmenting neuronal cell death. Blockade of δ-secretase cleavage of UNC5C diminishes T835M mutant's proapoptotic activity. Viral expression of δ-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, δ-secretase truncates UNC5C and elevates its neurotoxicity, contributing to AD pathogenesis.

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