A 42-year-old woman comes to the neurologist for enrollment in a research study. She has a 15-year history of resting tremor, bradykinesia, and cogwheel rigidity consistent with Parkinson's disease. One of her siblings recently started having similar symptoms. Genetic analysis is performed on the patient and her affected sibling. The results show a loss-of-function mutation in a gene that leads to an accumulation of misfolded proteins. Which of the following biochemical processes is most likely defective in this patient?

Question

A 42-year-old woman comes to the neurologist for enrollment in a research study.  She has a 15-year history of resting tremor, bradykinesia, and cogwheel rigidity consistent with Parkinson's disease.  One of her siblings recently started having similar symptoms.  Genetic analysis is performed on the patient and her affected sibling.  The results show a loss-of-function mutation in a gene that leads to an accumulation of misfolded proteins.  Which of the following biochemical processes is most likely defective in this patient?

Quizplus · Accepted Answer

11ec160b_36c0_34de_9249_87ac37d93103_MD0001_00 Ubiquitin is a protein found in all eukaryotic cells that undergoes ATP-dependent attachment to other proteins, labeling them for degradation. The proteasome then recognizes these ubiquinated proteins and uses ATP energy to drive them through its tubular structure, degrading them into small peptides in the process. Attachment of 4 or more ubiquitin monomers is required before most proteins are allowed entry into the proteasome. Ubiquitination plays an important role in many cell functions, including antigen processing, muscle wasting, cell cycle regulation, DNA repair, and disposal of misfolded proteins and regulatory enzymes. Impairment of the ubiquitin-proteasome system can contribute to the development of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Failure of the system to properly degrade abnormal proteins causes protein misfolding, aggregation, and eventual obstruction of intracellular molecular traffic, leading to cell death. Together, the Parkin, PINK1, and DJ-1 genes code for a protein complex that promotes the degradation of misfolded proteins via the ubiquitin-proteasome system. Mutations in Parkin, PINK1, and DJ-1 are each associated with autosomal recessive forms of Parkinson's disease that have an early age of onset (< 50 years). (Choice A) Heterochromatin is condensed and methylated DNA that has a low level of transcriptional activity. In contrast to heterochromatin, euchromatin (loosely arranged chromatin) has very high levels of transcriptional activity. Histone acetylation promotes the formation of euchromatin. (Choice B) Vitamin K-dependent gamma-carboxylation is critical for the functioning of clotting factors II, VII, IX, and X, and of the anticoagulative proteins C and S. Warfarin inhibits carboxylation of these proteins. (Choice C) The hepatic processing of bilirubin is accomplished in three key steps: carrier-mediated passive uptake of bilirubin at the sinusoidal membrane; conjugation of bilirubin with glucuronic acid in the endoplasmic reticulum; and active biliary excretion of the water-soluble, nontoxic bilirubin-glucuronides. Disruption of this process occurs in Crigler-Najjar syndrome, a condition in which patients lack the enzyme needed to catalyze bilirubin glucuronidation. (Choice D) Phosphorylation is the addition of a phosphate group (PO₄^3-) to a protein or other organic molecule. Phosphorylation is commonly involved in the regulation of enzymatic activity. Educational objective: Ubiquitin is a protein that undergoes ATP-dependent attachment to other proteins, labeling them for degradation. These modified proteins enter the proteasome and are degraded into small peptides. Impairment of the ubiquitin-proteasome system can contribute to the development of neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. __________ References: Parkin and defective ubiquitination in Parkinson's disease. (http://www.ncbi.nlm.nih.gov/pubmed/17017531) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. (http://www.ncbi.nlm.nih.gov/pubmed/19229105)

A 42-Year-Old Woman Comes to the Neurologist for Enrollment in a Research