ER-phagy Endoplasmic Reticulum 4-PBA (PBA) 4-Phenylbutyrate

4-Phenylbutyrate (4-PBA) is an FDA-approved chemical chaperone that acts as a potent inhibitor of endoplasmic reticulum (ER) stress, a cellular state linked to neurodegeneration and metabolic diseases. By promoting proper protein folding, 4-PBA reduces protein aggregation, directly counteracting the need for, or assisting in, ER-phagy (selective autophagy of the ER) to manage misfolded proteins.

Key Aspects of 4-PBA in ER Stress Management:

Mechanism of Action: As a chemical chaperone, 4-PBA interacts with exposed hydrophobic segments of unfolded proteins, preventing their aggregation and facilitating correct folding.

ER Stress Reduction: It effectively reduces the accumulation of misfolded proteins in the ER, thereby limiting ER stress-induced apoptosis.

Therapeutic Applications: 4-PBA is utilized to treat urea cycle disorders and has shown promise in treating neurodegenerative diseases (Parkinson’s, Alzheimer's), as well as non-alcoholic fatty liver disease, chronic kidney disease, and ocular HSV-1.

Relationship to ER-phagy: While ER-phagy is a mechanism for removing damaged ER, 4-PBA serves as a protective, upstream agent that reduces the severity of stress, often decreasing the need for massive ER degradation.

4-PBA functions broadly to maintain cellular homeostasis and reduce the pathological impact of ER dysfunction.

Key 4-PBA Derivatives and Related Compounds

C5 (isopropyl 4-PBA): A modified derivative designed to cross the blood-brain barrier.

3-Phenylpropionate (3-PPA): A related short-chain fatty acid tested for chaperone activity.

5-Phenylvaleric acid: A longer-chain derivative studied for ER stress reduction.

6-Phenylhexanoic acid: A further lengthened derivative tested for protein aggregation inhibition