Question

CASE STUDY: Lysosomal Storage Disease

Ensuring that proteins are targeted to the proper cellular destination is critical in eukaryotic cell function. Not only is this necessary for the protein to be in the proper place to carry out its function but also because certain post-translation modifications take place in the secretory pathway. Therefore improperly processed proteins may be defective in their biochemical activity even if they are located in the proper place in the cell.

I-cell Disease (also called mucolipidosis) is a severe genetic abnormality caused by a deficiency in multiple enzymes within the lysosome. It is caused by a defect in the N-acetylglucosamine-1 phosphotransferase that makes mannose 6 phosphate residues on proteins destined for targeting to the lysosome. The lysosome is the cellular organelle where many proteins and glycolipids are degraded. In I-cell disease fibroblasts from patients are filled with large intracellular vesicles filled with glycolipids and extracellular components. The disease manifests in patients with severe psychomotor retardation and skeletal abnormalities.

Questions:

1. The N-acetylglucasamine-1 phosphotransferase normally acts in the Golgi. In I-Cell disease where will the enzymes normally destined for the lysosome be found?

2. When fibroblasts from patients suffering from I cell disease are cultured, they secrete lysosomal enzymes rather than accumulating them within lysosomes. When lysosomal enzymes containing Mannose-6-phosphate (M6P) are added to the culture, they are rapidly internalized and accumulate within lysosomes. Why can these cells target exogenous enzymes but not endogenous enzymes to lysosomes?

Answer 1

Answer:

1):

• Mannose-6-phosphate residues deliver enzymes from the Golgi apparatus to the lysosomes.
• In I-cell disease, the mannose-6-phosphate residues are not being made due to defective N-acetyglucosamine-1 phosphotransferase.
• Without mannose-6-phosphate, the enzymes are not targeted to the lysosomes.
• Rather, they are secreted into the extracellular space by the Golgi apparatus. H
• lysosomes in I-cell disease are deficient in several enzymes, leading to disease manifestation.

2):

• Absence of the enzyme disrupts the normal post- translational modification of lysosomal enzymes and deprives newly synthesized lysosomal enzymes of the mannose 6-phosphate recognition marker which is critical for receptor-mediated delivery to lysosomes.
• This results in an enhanced extracellular secretion and a decreased intracellular accumulation.

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