Clusterin protects neurons against intracellular proteotoxicity

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Clusterin, a secreted chaperone, is redirected to the cytosol during endoplasmic reticulum (ER) stress.
• The physiological role of this relocation in cellular defense is unknown.
• Protein aggregation and cytotoxicity are hallmarks of neurodegenerative diseases.

Purpose of the Study:

• To investigate if increased clusterin expression protects neuronal cells against intracellular protein aggregation and cytotoxicity.
• To explore clusterin's effects on the aggregation of the amyotrophic lateral sclerosis-associated protein TDP-43.
• To assess clusterin's protective role in models mimicking neurodegenerative conditions.

Main Methods:

• In vitro protein interaction and aggregation assays using TDP-43.
• Studies in cultured neuronal cells under ER stress.
• Transgenic Drosophila models expressing TDP-43, Huntingtin, and mutant tau.
• Assessment of protein localization, cellular stress, motor function, and lifespan.

Main Results:

• Clusterin directly interacts with TDP-43, inhibiting its aggregation in vitro.
• In ER-stressed neuronal cells, clusterin co-localized with TDP-43 and reduced cytoplasmic inclusions.
• In Drosophila, clusterin co-expression cleared mislocalized TDP-43, improved motor activity, and extended lifespan.
• Clusterin provided ER stress-dependent protection against Huntingtin and mutant tau proteotoxicity in Drosophila photoreceptor cells.

Conclusions:

• Increased clusterin expression confers protection against intracellular proteotoxicity.
• Clusterin acts as a defense mechanism in cellular conditions mimicking neurodegenerative diseases.
• The cytosolic relocation of clusterin during ER stress is a protective response against protein aggregation.