Cell Disease Results From Faulty Targeting of Lysosomal Enzymes

As indicated above, Man 6-P serves as a chemical marker to target certain lysosomal enzymes to that organelle. Analysis of cultured fibroblasts derived from patients with I-cell (inclusion cell) disease played a large part in revealing the above role of Man 6-P. I-cell disease is an uncommon condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade. Cultured cells from patients with I-cell disease were found to lack almost all of the normal lysosomal enzymes; the lysosomes thus accumulate many different

Figure 47-13. Scheme of causation of paroxysmal nocturnal hemoglobinuria (MIM 311770).

types of undegraded molecules, forming inclusion bodies. Samples of plasma from patients with the disease were observed to contain very high activities of lysosomal enzymes; this suggested that the enzymes were being synthesized but were failing to reach their proper intracellular destination and were instead being secreted. Cultured cells from patients with the disease were noted to take up exogenously added lysosomal enzymes obtained from normal subjects, indicating that the cells contained a normal receptor on their surfaces for endocytic uptake of lysosomal enzymes. In addition, this finding suggested that lysosomal enzymes from patients with I-cell disease might lack a recognition marker. Further studies revealed that lysosomal enzymes from normal individuals carried the Man 6-P recognition marker described above, which interacted with a specific intracellular protein, the Man 6-P receptor. Cultured cells from patients with I-cell disease were then found to be deficient in the activity of the cis Golgi-located GlcNAc phosphotransferase, explaining how their lysosomal enzymes failed to acquire the Man 6-P marker. It is now known that there are two Man 6-P receptor proteins, one of high (275 kDa) and one of low (46 kDa) molecular mass. These proteins are lectins, recognizing Man 6-P. The former is cation-independent and also binds IGF-II (hence it is named the Man 6-P-IGF-II receptor), whereas the latter is cation-dependent in some species and does not bind IGF-II. It appears that both receptors function in the intracellular sorting of lysosomal enzymes into clathrin-coated vesicles, which occurs in the trans Golgi subsequent to synthesis of Man 6-P in the cis Golgi. These vesicles then leave the Golgi and fuse with a prelysoso-mal compartment. The low pH in this compartment causes the lysosomal enzymes to dissociate from their receptors and subsequently enter into lysosomes. The receptors are recycled and reused. Only the smaller receptor functions in the endocytosis of extracellular lysosomal enzymes, which is a minor pathway for lysosomal location. Not all cells employ the Man 6-P receptor to target their lysosomal enzymes (eg, hepatocytes use a different but undefined pathway); furthermore, not all lysosomal enzymes are targeted by this mechanism. Thus, biochemical investigations of I-cell disease not only led to elucidation of its basis but also contributed significantly to knowledge of how newly synthesized proteins are targeted to specific organelles, in this case the lysosome. Figure 47-14 summarizes the causation of I-cell disease.

Pseudo-Hurler polydystrophy is another genetic disease closely related to I-cell disease. It is a milder condition, and patients may survive to adulthood. Studies have revealed that the GlcNAc phosphotrans-ferase involved in I-cell disease has several domains, including a catalytic domain and a domain that specifi-

Mutations in DNA

Mutant GlcNAc phosphotransferase

Lack of normal transfer of GlcNAc 1-P to specific mannose residues of certain enzymes destined for lysosomes

These enzymes consequently lack Man 6-P and are secreted from cells (eg, into the plasma) rather than targeted to lysosomes

Lysosomes are thus deficient in certain hydrolases, do not function properly, and accumulate partly digested cellular material, manifesting as inclusion bodies

Figure 47-14. Summary of the causation of I-cell disease (MIM 252500).

cally recognizes and interacts with lysosomal enzymes. It has been proposed that the defect in pseudo-Hurler polydystrophy lies in the latter domain, and the retention of some catalytic activity results in a milder condition.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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