Related Experiment Video

Updated: Jun 2, 2025

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
06:58

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

574

The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease

Hongtao Shen1,2, Yuying Xie1, Yan Wang1

  • 1Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

Autophagy
|January 15, 2025
PubMed

Insights

Calnexin (CANX) interacts with ULK1 to initiate autophagy. Loss of CANX impairs autophagy and cognitive function in Alzheimer's disease models, while its restoration improves these deficits.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • The link between autophagy and Alzheimer's disease (AD) is recognized, but the specific regulatory mechanisms, particularly at the autophagy initiation stage, remain unclear.
  • Understanding how autophagy is regulated is crucial for developing therapeutic strategies for AD.

Purpose of the Study:

  • To investigate the role of ER transmembrane protein Calnexin (CANX) in autophagy initiation and its implications for Alzheimer's disease.
  • To identify novel interaction partners of the autophagy-inducing kinase ULK1.

Main Methods:

  • Immunoprecipitation (IP) and bimolecular fluorescence complementation (BiFC) to identify CANX as a ULK1 interaction partner.
  • Cellular assays to assess autophagy flux and ULK1 kinase activity in CANX-deficient cells.
  • Studies in APP-PSEN1 transgenic mice and C57BL/6 mice to evaluate the impact of CANX on neuronal function and cognitive behavior.

Main Results:

  • Calnexin (CANX) directly interacts with ULK1, facilitating ULK1 recruitment to the ER and promoting autophagy initiation.
  • Loss of CANX leads to ULK1 inactivation, impaired autophagy flux, accumulation of autophagy receptors, and neuronal damage.
  • Reduced CANX-ULK1 interaction is observed in human AD brains and APP-PSEN1 mice.
  • CANX deficiency in hippocampal neurons impairs cognitive function in mice.
  • Overexpression of CANX enhances autophagy and improves cognitive function in APP-PSEN1 mice, dependent on its interaction domain with ULK1.

Conclusions:

  • Calnexin (CANX) is a critical regulator of autophagy initiation by cooperating with ULK1.
  • CANX plays a significant role in maintaining neuronal health and cognitive function.
  • Targeting the CANX-ULK1 interaction presents a potential therapeutic avenue for Alzheimer's disease.
Keywords:
Alzheimer diseaseERULK1autophagy initiationcalnexin

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