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

Authors

Guiqin Chen, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Seong Su Kang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zhihao Wang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Eun Hee Ahn, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yiyuan Xia, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xia Liu, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ivette M. Sandoval, Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, USA.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, USA.Follow
Zhaohui Zhang, Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China. kye@emory.edu zhzhqing1990@163.com.
Keqiang Ye, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. kye@emory.edu zhzhqing1990@163.com.

Document Type

Article

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.

Publication Date

4-1-2021

Publication Title

Science advances

E-ISSN

2375-2548

Volume

7

Issue

16

PubMed ID

33863723

Digital Object Identifier (DOI)

10.1126/sciadv.abe4499

Recommended Citation

Chen, Guiqin; Kang, Seong Su; Wang, Zhihao; Ahn, Eun Hee; Xia, Yiyuan; Liu, Xia; Sandoval, Ivette M.; Manfredsson, Fredric P.; Zhang, Zhaohui; and Ye, Keqiang, "Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies" (2021). Translational Neuroscience. 1437.
https://scholar.barrowneuro.org/neurobiology/1437