Ageing research reviewsOct 23, 2026

Selective Removal of Cell Stress Structures by Receptors in Brain Diseases: How It Works and Possible Treatments

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 24, 2026

Abstract

Neurodegenerative diseases are associated with the accumulation of altered proteins that disrupt cellular function.

Neurodegenerative diseases, driven by increased life expectancy, are linked to the lack of therapies that modify disease progression.
The accumulation of misfolded proteins contributes to cellular dysfunction and neuronal loss.
Sustained stress in the endoplasmic reticulum (ER) is implicated in the progression of neurodegenerative diseases.
ER-selective autophagy (ER-phagy) serves as a critical pathway for maintaining protein quality and cellular integrity in neurons.
The specific roles of different receptors involved in ER-phagy and their regulatory networks are not fully understood.
Modulating receptor-specific ER-phagy may offer a new therapeutic approach to alleviate ER stress and support neuronal health.

Simplified

Neurodegenerative diseases (NDs) constitute a major global health burden driven by rising life expectancy and the lack of disease-modifying therapies. Central to these progressive pathologies is the accumulation and aggregation of conformationally altered proteins, categorizing them as 'proteinopathies'. These aberrant aggregates disrupt cellular homeostasis and trigger chronic stress responses that drive progressive neuronal dysfunction and loss. The endoplasmic reticulum (ER) is a dynamic organelle defined by remarkable structural diversity and functional plasticity, that preserves cellular homeostasis by orchestrating protein folding and quality control, lipid biosynthesis, calcium sequestration and metabolic detoxification. However, sustained ER stress and functional dysregulation are increasingly implicated in neurodegenerative cascades. In this context, ER-selective autophagy (ER-phagy) has emerged as an indispensable quality-control pathway. Mediated by dedicated ER-phagy receptors that target distinct subdomains for lysosomal clearance, this pathway preserves organellar integrity and mitigates proteotoxic burden in post-mitotic neurons. Nonetheless, the full mechanistic landscape of ER-phagy remains poorly defined, with receptor-specific functions, regulatory signalling networks and CNS expression profiles only beginning to be resolved. This review synthesizes current insights into ER-phagy in neurodegeneration, dissects receptor-specific mechanisms, and highlights emerging pharmacological interventions. Ultimately, the therapeutic potential of modulating receptor-specific ER-phagy as an untapped strategy to resolve ER stress, re-establish neuronal proteostasis and to combat neurodegenerative conditions is highlighted.

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Selective Removal of Cell Stress Structures by Receptors in Brain Diseases: How It Works and Possible Treatments

Abstract

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