Mutations in Parkinson disease pathology
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Mutations in Parkinson disease pathology
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[ID] => 553879
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[post_date] => 2024-12-23 09:16:57
[post_date_gmt] => 2024-12-23 14:16:57
[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.
Neurodegeneration, the continuous loss of neuronal structure and function, is responsible for a number of mental illnesses, including Parkinson disease and Alzheimer disease. In both of these diseases, the aggregation of specific proteins leads to the death of neurons and the disruption of normal brain function. Researchers studied a German family with a history of Parkinson disease in order to better understand the pathology of the disease. Figure 1 shows a pedigree analysis of the family, where shaded individuals have developed Parkinson disease.
Figure 1 Pedigree analysis
Upon studying biopsies obtained from diseased family members, the researchers found an abnormal aggregation of α-synuclein in the brain. Although the exact function of α-synuclein is currently unknown, the protein is thought to be normally involved in spatial learning, working memory, synaptic rearrangement, and dopamine regulation. Figure 2 shows a pedigree analysis of the German family, where shaded individuals have developed Parkinson's disease.
Upon PCR analysis, it was discovered that a mutation in the ubiquitin carboxy-terminal hydrolase L1 gene (UCH-L1) was present in the family members that had Parkinson's disease. The isoleucine at position 93 (codon ATC) was changed to a methionine (codon ATG). Researchers then expressed the mutant and wild-type UCH-L1 proteins in E. coli cells. The catalytic activity of each protein is shown in Table 1.
Table 1 Catalytic activity and molecular weight of the wild-type or mutant protein; U = 1 μmol min⁻¹
Immunohistochemistry of midbrain sections of a patient with Parkinson disease showed α-synuclein and UCH-L1 double-positive Lewy bodies, abnormal protein aggregates in mesencephalon dopaminergic neurons, suggesting physical and/or functional interaction between the two proteins leads to Parkinson disease.
Source: Leroy, E. Boyer, R. Auburger, G. Leube, B. Ulm, G. Mezey, E. et al. (1998). The ubiquitin pathway in Parkinson's disease. Nature, 451-452.
Yasuda T1, Nihira T, Ren YR, Cao XQ, Wada K, Setsuie R. et al. (2009).Effects of UCH-L1 on alpha-synuclein over-expression mouse model of Parkinson's disease. Journal of neurochemistry, 932-944.
[post_title] => Mutations in Parkinson disease pathology
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[question] => Which of the following most likely explains the inheritance pattern shown in the pedigree?
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[answer] => 3
[description] => Reason for Correct Answer:
An X-linked trait would result in sex differences in phenotype frequency. There are an equal amount of males and females with the condition, so the trait is not X-linked.
Because mitochondria are solely inherited from the mother, all offspring would exhibit the same phenotype as the mother. One son in the second generation does not have his mother’s phenotype, so it does not have a mitochondrial pattern.
The female in generation 2 being a carrier for a separate mutation would not contribute to the children inheriting this condition (i.e. if this were autosomal recessive, it would take two mutations of the same gene to create the disease).
The best explanation is therefore incomplete penetrance. Incomplete penetrance means that the carrier of the gene mutation will sometimes but not always develop the disease. This could explain why the father in generation 2 doesn’t have the disease but his offspring do.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The female in generation 2 is a carrier for a mutation in another Parkinson’s related gene.
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[1] => Array
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[each_answer] => B. arrest in the development of B lymphocytes at the early stage of large pre-B-cells.
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[2] => Array
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[each_answer] => C. The UCH-L1 mutation has incomplete penetrance.
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[each_answer] => D. Parkinson disease is a sex-linked condition.
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => What type of mutation is found in the mutant UCH-L1?
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[answer] => 3
[description] => Reason for Correct Answer:
A silent mutation would have no effect on the final protein product.
A nonsense mutation would result in an incomplete protein. Because both the wild-type and the mutant have the same molecular weight, there are no missing amino acids.
Point mutations do not shift the reading frame, as they are a single-base substitution.
The mutation of interest converts isoleucine at position 93 (codon ATC) to a methionine (codon ATG). This is a missense mutation (change in one amino acid) caused by a point mutation of C->G.
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[answers] => Array
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[0] => Array
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[each_answer] => A. A point mutation that shifts the reading frame
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[1] => Array
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[each_answer] => B. An insertion that causes a nonsense mutation
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[2] => Array
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[each_answer] => C. A single-base substitution that causes a missense mutation
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[each_answer] => D. A deletion that results in a silent mutation
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => What additional data would counter the suggested role of α-synuclein in Parkinson development?
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[answer] => 1
[description] => Reason for Correct Answer:
One suggested function of α-synuclein is synaptic rearrangement. Children and young adults undergo synaptic pruning, so upregulation is expected.
α-synuclein clearly has multiple roles, and its function is not fully understood. The heart and other body parts may require dopamine regulation, and so presence of α-synuclein in these areas is normal.
Ubiquitination is a form of degradation, which is what the passage is about. Because α-synuclein is aggregating in the brain, this would result in neurodegeneration, which is expected.
Family members with Parkinson disease were characterized by the UCH-L1 mutation and aggregation of α-synuclein. If α-synuclein aggregation were seen in family members without any Parkinson symptoms, it could call into question the causal role of α-synuclein in Parkinson development. (Although it would not rule out α-synuclein as a causal factor, as these individuals may not have enough aggregation to lead to Parkinson, or they may have additional protective factors.)
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[answers] => Array
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[0] => Array
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[each_answer] => A. In a follow-up study, α-synuclein aggregation is found in family members who did not have Parkinson symptoms.
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[1] => Array
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[each_answer] => B. α-synuclein is found in heart and muscle tissue of healthy individuals.
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[2] => Array
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[each_answer] => C. It is discovered that the presence of α-synuclein aggregation increases ubiquination.
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[each_answer] => D. α-synuclein upregulation is found in children undergoing puberty.
)
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[3] => Array
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[quiz_unique_key] => 1403770772
[question] => What is the most likely function of the UCH-L1 protein?
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[answer] => 2
[description] => Reason for Correct Answer:
This question seems complicated, but only requires basic information from the passage. The full name of UCH-L1 is ubiquitin carboxy-terminal hydrolase L1.
Hydrolases break down bonds, consuming a water molecule in the process. Here is the general reaction catalyzed:
An ubiquitin hydrolase would break bonds, such as removing ubiquitin from target molecules.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The attachment of ubiquitin molecules to target proteins
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[1] => Array
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[each_answer] => B. The removal of ubiquitin molecules from target proteins
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[2] => Array
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[each_answer] => C. The phosphorylation and activation of ubiquitin
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[3] => Array
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[each_answer] => D. The activation of ubiquitin via an induced bond rearrangement
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[quiz_unique_key] => 1403770772
[question] => According to its function, what is most likely a direct effect of a UCH-L1 mutation?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The answer to the last question was that the UCH-L1 protein deubiquinates proteins.
Normally, ubiquination tags proteins for proteasomal degradation.
This means that UCH-L1 usually prevents protein degradation.This means that a UCH-L1 mutation would increase proteasomal protein degradation. In the case of Parkinson disease, this can lead to complex downstream effects.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Decreased degradation of proteins
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[1] => Array
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[each_answer] => B. Increased degradation of proteins
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[2] => Array
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[each_answer] => C. Inhibition of proper protein folding
)
[3] => Array
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[each_answer] => D. Decreased protein aggregation
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[quiz_unique_key] => 1403770772
[question] => What might be the most effective treatment to prevent neurodegeneration?
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[answer] => 1
[description] => Reason for Correct Answer:
A deletion of a single base from the methionine codon would be a frame-shift mutation, destroying the integrity of the UCH-L1 protein.
Upregulation of the mutated, defective UCH-L1 protein would also not help.
The passage suggests that α-synuclein aggregates in the brain cause Parkinson disease
Therefore, immunotherapy that induces the clearance of aggregated α-synuclein would be most likely to work. Immunotherapies work by stimulating the immune system (e.g. macrophages) to recognize and clear these pathological proteins, potentially slowing down or halting the disease progression.
Hormones, on the other hand, typically do not have the same level of specificity for targeting protein aggregates, and their mechanisms of action may not be as directly related to protein clearance. While some hormones may have indirect effects on cellular processes involved in protein degradation, they are not typically the primary focus in efforts to clear protein aggregates.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Immunotherapy designed to enhance the immune system’s response to aggregated α-synuclein
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[1] => Array
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[each_answer] => B. A single base deletion codon 93, to remove the new methionine from mutated UCH-L1
)
[2] => Array
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[each_answer] => C. Deliberate upregulation of the UCH-L1 found in Parkinson’s patients
)
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[each_answer] => D. An ingested hormone that induces the destruction of protein aggregates
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Figure 1
