Lysosomal storage disease NPC
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Lysosomal storage disease NPC
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[ID] => 554019
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[post_date] => 2024-12-23 17:46:22
[post_date_gmt] => 2024-12-23 22:46:22
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Niemann–Pick type C (NPC) disease is a rare, autosomal recessive lysosomal storage disorder that is predominantly caused by mutations in the NPC1 gene, which codes for the 133-kilodalton (kDa) protein NPC1 and in rarer cases caused by mutations in the NPC2 gene, which codes for the 14.9-kDa protein NPC2. Defects in lipid transport in lysosomes and late endosomes are most likely critical to disease pathogenesis. Cholesterol has been widely recognized as the major storage lipid involved, and sphingomyelin and glycosphingolipid involvement have also been characterized in both animal models and patients with NPC. The isolation of the NPC1 and NPC2 genes has allowed for elucidation of the role played by NPC proteins in cholesterol transport.
Neurons are known to obtain cholesterol through endogenous synthesis or uptake of lipoprotein cholesterol particles produced and released within the central nervous system (CNS). Following the internalization of these particles by target cells, unesterified cholesterol is transported from the endosomal/lysosomal system to the Golgi complex and endoplasmic reticulum, where it is processed and used as a substrate for further reactions. Brown and Goldstein suggested that the NPC1 and NPC2 proteins perform coordinated actions during this process – NPC2 binds unesterified cholesterol and transfers it to the N-terminal domain of membrane-associated NPC1, thereby allowing its transport out of the late endosome/lysosome compartment. However, in the absence of NPC1 and NPC2, lipoprotein cholesterol particles remain trapped in late endosome/lysosome system, greatly reducing cholesterol levels in the Golgi complex and endoplasmic reticulum and causing deleterious effects on all processes that depend on proper membrane composition.
Effects of cholesterol transport in Niemann–Pick disease type C are illustrated in Figure 1.
Figure 1 Altered cholesterol trafficking in normal conditions (A) and in the absence of NPC1 or NPC2 (B)
Source: Cariati et al. Int. J. Mol. Sci. 2021, 22(12), 6600; https://doi.org/10.3390/ijms22126600
[post_title] => Lysosomal storage disease NPC
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[question] => Mutations in NPC1 and NPC2 result in:
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[answer] => 1
[description] => Reason for Correct Answer:
Retrograde transport moves materials from endosomes and lysosomes back to earlier compartments in the cell, such as the Golgi apparatus and endoplasmic reticulum. It plays a crucial role in recycling cellular components and maintaining proper cellular function. Anterograde transport, on the other hand, involves the movement of materials from the endoplasmic reticulum to the Golgi apparatus and then to various destinations within the cell, including the plasma membrane. Both retrograde and anterograde transport are essential for maintaining cellular organization and functionality.
In the case of NPC, there are defects in moving cholesterol from the outside of the cell to the Golgi and ER via lysosomes. These are defects in retrograde transport.
The passage says that this leads to “greatly reduced cholesterol levels,” or cholesterol deficiencies, in the Golgi and ER.
At the same time, cholesterol will build up or accumulate in endosomes and lysosomes.
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[answers] => Array
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[each_answer] => A. defects in retrograde transport, resulting in cholesterol buildup and deficiency in different cellular compartments.
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[each_answer] => B. defects in retrograde transport, resulting in cholesterol deficiencies in the plasma membrane.
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[each_answer] => C. defects in anterograde transport, resulting in cholesterol deficiencies in the plasma membrane.
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[each_answer] => D. defects in anterograde transport, resulting in cholesterol deficiencies in various organelles.
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => What type of protein would NPC1L1 protein likely be?
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[answer] => 2
[description] => Reason for Correct Answer:
The passage says that NPC1 binds cholesterol, thereby allowing its transport out of the late endosome/lysosome compartment.
Trafficking or membrane transport is likely mediated by components that go through the entire membrane.
Integral proteins are the only component that affect membrane transport/trafficking and they are a membrane component that passes all the way through the cell membrane. NPC1 is a transmembrane protein that spans the lipid bilayer of certain cellular compartments’ membranes.
Reason for Incorrect Answer:
A. Peripheral proteins, also known as extrinsic proteins, are proteins that are temporarily or loosely associated with the lipid bilayer of cell membranes. Peripheral proteins are not embedded within the lipid bilayer. This answer is less likely for proteins involved in transporting a molecule through a membrane.
C. Soluble proteins are those that are not associated with cellular membranes and are found in the cytoplasm or in various cellular compartments as soluble molecules. NPC2 is a soluble protein because it is free-floating in the lumen of the endosome and lysosome.
D. Scaffold proteins serve as frameworks for organizing other proteins into functional complexes or signaling pathways within cells. NPC1’s main function is related to cholesterol transport, and it is not primarily known for its role as a scaffold protein.
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[each_answer] => A. Peripheral protein
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[each_answer] => B. Integral protein
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[each_answer] => C. Scaffold protein
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[each_answer] => D. Transcription factor
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[quiz_unique_key] => 1403770772
[question] => Where does cholesterol esterification usually occur?
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[answer] => 3
[description] => Reason for Correct Answer:
Figure 1 shows unesterified and esterified cholesterol in different places of the cell.
As shown in the figure, cholesterol is only present in its esterified form in the Golgi and ER (it can travel between these organelles).
Cholesterol esterification usually occurs in the endoplasmic reticulum. The process of cholesterol esterification involves attaching a fatty acid to the hydroxyl group of cholesterol, and this reaction is catalyzed by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT). ACAT is primarily located in the ER membranes, making the ER the main site for cholesterol esterification.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Late endosome
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[each_answer] => B. Lysosome
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[each_answer] => C. Endoplasmic reticulum
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[each_answer] => D. Cytoplasm
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[quiz_unique_key] => 1403770772
[question] => The ‘fluidity’ of purified membranes can be determined by measuring the steady-state anisotropy of DPH (1,6-diphenyl-1,3,5-hexatriene), a fluorescent probe that is sensitive to the viscosity and rigidity of its environment. Researchers found that hepatocyte plasma membranes taken from a mouse model of NPC were less fluid at high temperatures than control membranes as indicated by increased DPH anisotropy.
Which statement is consistent with this finding?
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[answer] => 1
[description] => Reason for Correct Answer:
The question states that the NPC hepatocyte membranes were less fluid at high temperatures than control membranes, resulting in increased DPH anisotropy, indicating that DPH anisotropy is inversely proportional to membrane fluidity.
Cholesterol affects the fluidity of membranes in a bidirectional manner. At high temperatures, cholesterol decreases membrane fluidity (at high temperatures the phospholipids become less ordered and cholesterol decreases this effect). At low temperatures, cholesterol increases membrane fluidity (at low temperatures the phospholipids pack together tightly and cholesterol decreases this effect).
This means that the NPC hepatocytes had higher cholesterol, since they had decreased fluidity at high temperatures. It also means that DPH anisotropy is directly proportional to the cholesterol/phospholipid ratio at high temperatures.
Though Choice B could hypothetically happen in other cell types or other hepatocytes, the only answer consistent with the increased membrane cholesterol observed in this study is that the endosomal cholesterol transport block associated with NPC is leaky, such that the plasma membrane might eventually become cholesterol-engorged.
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[each_answer] => A. In hepatocytes, the endosomal cholesterol transport block associated with NPC is leaky, such that the plasma membrane might eventually become cholesterol-engorged.
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[each_answer] => B. Decreased cholesterol reaching the Golgi and ER leads to decreased trafficking of cholesterol to the hepatocyte cell membrane in the mice studied.
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[each_answer] => C. DPH anisotropy is inversely proportional to the cholesterol/phospholipid ratio of cell membranes at high temperatures.
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[each_answer] => D. DPH anisotropy is directly proportional to membrane fluidity.
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[quiz_unique_key] => 1403770772
[question] => What occurs during the transition from a late endosome to a lysosome?
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[answer] => 4
[description] => Reason for Correct Answer:
During the transition from a late endosome to a lysosome, several key processes occur to transform the organelle into a functional lysosome.
One crucial step is the activation of proton pumps, also known as vacuolar ATPases, present in the endosomal membrane.
These proton pumps actively transport protons (H+ ions) into the endosome’s lumen, leading to a decrease in its pH. As the luminal pH becomes more acidic, it creates an environment that is optimal for the function of lysosomal enzymes.
Concurrently, the low pH within the maturing endosome activates the hydrolytic enzymes stored within the organelle. These enzymes, also known as lysosomal hydrolases, are responsible for breaking down various macromolecules, including proteins, nucleic acids, lipids, and carbohydrates.
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[each_answer] => A. The endosome fuses with the Golgi apparatus, leading to the secretion of lysosomal enzymes into the extracellular space.
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[each_answer] => B. Enzymes responsible for breaking down lipids are downregulated, leading to an increase in lipid accumulation within the endosome.
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[each_answer] => C. The endosome’s luminal pH becomes more alkaline, creating an environment suitable for cargo recycling.
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[each_answer] => D. The endosome’s luminal pH becomes more acidic due to the action of proton pumps, and hydrolytic enzymes are activated.
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[quiz_unique_key] => 1115843717
[question] => During an experiment to analyze NPC, scientists used rate-zonal density gradient ultracentrifugation to analyze the molecular components of cells of the small intestine. This technique separates molecules based on their molecular size. Which component of a cell membrane would scientists expect to find closest to the bottom of the test tube?
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[answer] => 1
[description] => Reason for Correct Answer:
The passage states that NPC1 is a 133-kDa protein, whereas NPC2 is a 14.9-kDa protein.
Both of these proteins would be significantly larger than cholesterol and phospholipids.
As mentioned in the question, rate-zonal density gradient ultracentrifugation separates components based on their size (or, more accurately, their hydrodynamic volume). In this context, larger components will migrate towards the bottom of the tube during centrifugation, while smaller components will remain closer to the top.
Among the given options, the largest protein (NPC1) would be found at the bottom of the tube after centrifugation, whereas the smallest components (phospholipids and cholesterol) would be found at the top of the tube.
It’s important to note that while this explanation holds true in a general sense, the actual outcome could be influenced by factors such as the centrifugation conditions used, the density of the sample, and the presence of other molecules.
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[answers] => Array
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[each_answer] => A. NPC1 protein
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[each_answer] => B. NPC2 protein
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[each_answer] => C. Phospholipids
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[each_answer] => D. Cholesterol
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Figure 1