ER-phagy
Reticulophagy
Endoplasmic Reticulum
Autophagy
Lysosome
Lysosomal
Hydrolase
Enzyme
Acid pH 5.0
Lipase
Protease
Nuclease
Glycosidase
Phagophore
Autophagosome
Autolysosome
Endolysosome
Endosome

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ERLAD (ER-to-Lysosome-Associated Degradation)

ER-derived vesicles containing misfolded proteins (Procollagen)

ER-to-Lysosome-Associated Degradation (ERLAD): A mechanism involving the direct transport of ER-derived vesicles to endolysosomes for degradation, often used for clearing misfolded protein aggregates that resist standard ER-associated degradation (ERAD).

Lysosomes: The final destination where acidic hydrolases break down the ER cargo.

Key Components & Roles
ER-Phagy Receptors: Specialized proteins (e.g., FAM134B, SEC62, RTN3) bridge the ER membrane to the autophagy machinery by binding to LC3/GABARAP.

Lysosomes: The final destination where acidic hydrolases break down the ER cargo.

Endolysosomes: Hybrid organelles formed by the fusion of late endosomes and lysosomes; they serve as the primary site for ERLAD and micro-ER-phagy degradation.

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Lysosome

Their primary responsibility is catabolic degradation of proteins, polysaccharides and lipids into their respective building-block molecules: amino acids, monosaccharides, and free fatty acids. The breakdown is done by enzymes, proteases, glycosidases and lipases.

ER-phagy (endoplasmic reticulum-specific autophagy) is a specialized autophagy pathway that breaks down and recycles damaged or excess ER components via lysosomal digestive enzymes, acting as a crucial quality control mechanism for cellular homeostasis, anti-aging, and potential lifespan extension. As cells age, decreased ER-phagy leads to accumulation of damaged, misfolded proteins and dysfunctional organelles, reducing longevity.

Mechanism of Action: The cell uses autophagy receptors to mark specific ER subdomains. These are engulfed in specialized vesicles that fuse with lysosomes, where acid hydrolase enzymes break down the damaged material into raw components for reuse.

Lysosomal hydrolases (acid hydrolases) break down these components at low pH.

Key Aspects of ER-phagy and Lysosomal Action:

Mechanism: ER fragments are sequestered into autophagosomes, which then fuse with lysosomes to form autolysosomes.

Lysosomal Hydrolases: Lysosomes contain hydrolase enzymes (lipases, proteases, nucleases, glycosidases) that operate at an acidic pH (approx. 5.0) to degrade the ER components.

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Procollagen misfolding in the endoplasmic reticulum (ER) causes collagen-related diseases (Osteogenesis Imperfecta) by triggering ER stress, leading to, or requiring clearance of, the misfolded proteins. Key chaperones such as HSP47 stabilize the triple helix, while N-glycans prevent aggregation during stress.

Alternative Pathway: When chaperones cannot fix the misfolding, the cell often relies on autophagy to degrade the accumulated, misfolded procollagen.

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4-PBA (PBA)
4-Phenylbutyrate
Phenylacetate
Phenyl Butyrate Acetate
Aromatic Fatty Acid

Glucose Pentaacetate Acetylated Sugar

Buphenyl
Pheburane
Olpruva

Phenylbutyrate
Phenylbutyramide
Phenylpropionate
Phenylpropionic
Phenylhexanoic
Phenylacetate
Phenylvaleric

Penicillin G
Benzylpenicillin
Aminopenicillanic Acid
Indole-3-Acetic Acid (IAA)
Morphogen (Auxin)

4-Phenylbutyrate (4-PBA) is an FDA-approved aromatic fatty acid primarily used to treat urea cycle disorders (sold as Buphenyl) by providing alternative nitrogen excretion pathways. Acting primarily as a chemical chaperone, alleviating endoplasmic reticulum (ER) stress, reducing protein misfolding, and inhibiting apoptosis. 4-PBA shows potential for treating neurodegenerative diseases (Alzheimer’s, Parkinson’s), cardiovascular, and renal conditions.

It aids in protein folding, potentially treating neurodegenerative diseases, diabetes, and viral infections.

Mechanism of Action: Functions as a chemical chaperone that reduces ER-mediated stress and stabilizes mutant proteins. It also acts as a histone deacetylase (HDAC) inhibitor.

Medical Uses: Approved for urea cycle disorders (UCDs), acting as an alternative pathway to the urea cycle for nitrogen excretion. It is also investigated for ALS, cystic fibrosis, and various protein-misfolding diseases.

Therapeutic Potential: Research suggests 4-PBA has broad-spectrum potential in neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's), diabetes, and antiviral applications (HSV-1).

Clinical Use: Used to manage urea cycle disorders (UCD) by converting to phenylacetate, which binds glutamine to eliminate excess nitrogen.

It is also used to treat Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig's disease), and is being investigated for treating thyroid hormone transporter (MCT8) deficiencies, diabetes-related insulin resistance, and various cancers.

Phenylacetate (Phenylacetic Acid): A chemical found in plants (auxins) and used in the synthesis of pharmaceuticals, perfumes, and penicillin G.

Auxins are a class of plant hormones (or plant-growth regulators) with some morphogen-like characteristics.

Morphogens are produced by source cells and diffuse through surrounding tissues in an embryo during early development, such that concentration gradients are set up. These gradients drive the process of differentiation of unspecialised stem cells into different cell types, ultimately forming all the tissues and organs of the body. The control of morphogenesis is a central element in evolutionary developmental biology.

Auxin acts as a key plant morphogen and phytohormone, establishing concentration gradients (maxima) that dictate positional information, stem cell niche maintenance, and organogenesis. It regulates stem cell activity by directing cell division, differentiation, and promoting founder cell identity, such as in root, shoot, and vascular development.