Related Experiment Video

Updated: Jul 14, 2025

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
07:20

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy

Published on: January 31, 2025

518

Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the

Jin Wu1, Yingying Han1, Hao Xu1

  • 1Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China.

Science Advances
|October 6, 2023
PubMed

Insights

Chaperone-mediated autophagy (CMA) activation suppresses neuroinflammation by degrading p300, reducing microglial activation and neuronal damage in Parkinson's disease models.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Neuroinflammation is a key factor in Parkinson's disease progression.
  • Chaperone-mediated autophagy (CMA) dysfunction is linked to pro-inflammatory effects.
  • The precise role of CMA in microglial activation and neuroinflammation requires clarification.

Purpose of the Study:

  • To investigate the mechanism by which CMA modulates microglial activation and neuroinflammation.
  • To determine if CMA influences microglia-mediated neuronal damage.
  • To explore the therapeutic potential of CMA activation in Parkinson's disease.

Main Methods:

  • Assessed LAMP2A levels in lipopolysaccharide (LPS)-treated primary microglia.
  • Utilized a CMA activator (CA) to modulate CMA activity.
  • Identified p300 as a CMA substrate using proteomic analysis.
  • Examined p65 acetylation and NLRP3 inflammasome activation.
  • Evaluated neuronal death in vitro and in vivo models.

Main Results:

  • LAMP2A, a crucial CMA protein, was reduced in LPS-treated microglia.
  • CMA activation by CA repressed LPS-induced microglial activation.
  • CMA dysfunction exacerbated microglial activation.
  • CMA degrades p300, reducing p65 acetylation and inhibiting pro-inflammatory factors and NLRP3 inflammasome activation.
  • CA pretreatment reduced microglia-mediated inflammation and attenuated neuronal death.

Conclusions:

  • CMA activation suppresses microglial activation via the p300-NF-κB pathway.
  • This study reveals a novel mechanism linking CMA to neuroinflammation in Parkinson's disease.
  • Targeting CMA represents a potential therapeutic strategy for neuroinflammatory conditions.

More Related Videos

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates09:12

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates

Published on: January 30, 2014

16.0K
Development of an Insert Co-culture System of Two Cellular Types in the Absence of Cell-Cell Contact11:29

Development of an Insert Co-culture System of Two Cellular Types in the Absence of Cell-Cell Contact

Published on: July 17, 2016

27.9K

Related Concept Videos

Delivery Pathways to the Lysosome01:36

Delivery Pathways to the Lysosome

Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
6.6K
Autophagy01:27

Autophagy

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
4.3K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.5K
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
3.4K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.6K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.5K