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Updated: May 28, 2026

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FAM134B-mediated ER-phagy degrades APP and suppresses Alzheimer's disease pathology

Yuting Zhang1, Jun Sun1, Yang Cai1

  • 1Department of Neurology, Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.

The EMBO Journal
|May 26, 2026
PubMed

Insights

FAM134B protein deficiency impairs endoplasmic reticulum autophagy (ER-phagy), leading to amyloid precursor protein (APP) accumulation and Alzheimer's disease (AD) pathology. Restoring FAM134B function in mice improves APP clearance and cognitive function.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Endoplasmic reticulum autophagy (ER-phagy) is crucial for cellular homeostasis.
  • The role of ER-phagy in Alzheimer's disease (AD) pathogenesis is not well understood.
  • Amyloid precursor protein (APP) accumulation is a hallmark of AD.

Purpose of the Study:

  • To investigate the role of ER-phagy in Alzheimer's disease.
  • To identify specific ER-phagy receptors involved in APP degradation.
  • To explore FAM134B as a potential therapeutic target for AD.

Main Methods:

  • Identified FAM134B as an ER-phagy receptor for APP.
  • Investigated FAM134B interaction with APP and LC3.
  • Analyzed FAM134B expression and epigenetic regulation in AD models.
  • Utilized AAV-mediated gene delivery in 5XFAD mice to assess FAM134B function.

Main Results:

  • FAM134B directly binds APP and mediates its lysosomal degradation via ER-phagy.
  • Epigenetic silencing of FAM134B in AD leads to impaired ER-phagy and APP accumulation.
  • Restoration of FAM134B in 5XFAD mice reduced Aβ deposition and improved cognitive function.
  • Wild-type FAM134B, but not LIR-mutant, rescued ER-phagy and ameliorated AD pathology.

Conclusions:

  • FAM134B downregulation is an upstream pathogenic event in Alzheimer's disease.
  • ER-phagy enhancement via FAM134B is a potential therapeutic strategy for AD.
  • Targeting FAM134B may reduce amyloid-beta generation at its source.

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