Passage
Alzheimer disease (AD) is a progressive condition affecting memory and cognition that can be pathologically characterized by the presence of neurofibrillary tangles (NFTs) . NFTs, aggregates of hyperphosphorylated tau proteins that have dissociated from microtubules, are believed to contribute to neuronal degradation and subsequent AD symptoms. In general, ribosomes initiate translation of tau mRNA by binding the 7-methylguanosine (m7Gpp) cap present at the end of the 5′ untranslated region (UTR) of the mRNA molecule. However, researchers believe that tau protein translation initiation can occur without recognition of the m7Gpp cap. This alternate mechanism, referred to as cap-independent translation, indicates that ribosomes are recruited by internal ribosome entry sites (IRES) generally located in the 5′ UTR of the mRNA sequence.To determine the initiation mechanism of tau mRNA translation, neuroblastoma cells of AD mice were transfected with two different DNA constructs (Figure 1) . Construct 1 contained the 5′ UTR of tau mRNA isoforms (v1 and v2) extracted from cells displaying NFTs. Construct 2 included the 5′ UTR of the β-globulin gene, which normally codes for a plasma protein. The luciferase reporter genes, Renillla and Photinus, were also included in the two constructs.
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Figure 1 DNA constructs containing β-globulin or tau gene used to transfect neuroblastoma cellsLuciferase gene expression from the constructs was monitored in the absence and presence of a synthetic m7Gpp cap analog (Figure 2) . Translation of Renillla luciferase mRNA depended on ribosomal binding to the m7Gpp cap of the mRNA, but translation of Photinus luciferase required ribosome recruitment by an IRES in the 5′ UTR of the adjacent gene.
Figure 2 Luciferase activity in neuroblastoma cells exposed to m7Gpp cap analogIn a second study, researchers used siRNA to target initiation factor eIF4E, a peptide translated in a cap-dependent manner that facilitates the binding of ribosomes to the m7Gpp cap. Expression of factor eIF4E, elongation factor eEF2K, and tau v2 protein was assessed in siRNA-treated cells (Figure 3) .
Figure 3 Western blot of eIF4E, eEF2K, and tau v2 extracted from non-AD cells treated with eIF4E siRNA
Adapted from Veo BL, Krushel LA. Translation initiation of the human tau mRNA through an internal ribosomal entry site. J Alzheimers Dis. 2009; 16(2) :271-5.
-Recently fed ob/ob mice show deficient binding of glucagon to its G protein-coupled receptor, which most likely leads to:

Question

Passage
Alzheimer disease (AD) is a progressive condition affecting memory and cognition that can be pathologically characterized by the presence of neurofibrillary tangles (NFTs) . NFTs, aggregates of hyperphosphorylated tau proteins that have dissociated from microtubules, are believed to contribute to neuronal degradation and subsequent AD symptoms. In general, ribosomes initiate translation of tau mRNA by binding the 7-methylguanosine (m7Gpp) cap present at the end of the 5′ untranslated region (UTR) of the mRNA molecule. However, researchers believe that tau protein translation initiation can occur without recognition of the m7Gpp cap. This alternate mechanism, referred to as cap-independent translation, indicates that ribosomes are recruited by internal ribosome entry sites (IRES) generally located in the 5′ UTR of the mRNA sequence.To determine the initiation mechanism of tau mRNA translation, neuroblastoma cells of AD mice were transfected with two different DNA constructs (Figure 1) . Construct 1 contained the 5′ UTR of tau mRNA isoforms (v1 and v2) extracted from cells displaying NFTs. Construct 2 included the 5′ UTR of the β-globulin gene, which normally codes for a plasma protein. The luciferase reporter genes, Renillla and Photinus, were also included in the two constructs.
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Figure 1 DNA constructs containing β-globulin or tau gene used to transfect neuroblastoma cellsLuciferase gene expression from the constructs was monitored in the absence and presence of a synthetic m7Gpp cap analog (Figure 2) . Translation of Renillla luciferase mRNA depended on ribosomal binding to the m7Gpp cap of the mRNA, but translation of Photinus luciferase required ribosome recruitment by an IRES in the 5′ UTR of the adjacent gene.

Figure 2 Luciferase activity in neuroblastoma cells exposed to m7Gpp cap analogIn a second study, researchers used siRNA to target initiation factor eIF4E, a peptide translated in a cap-dependent manner that facilitates the binding of ribosomes to the m7Gpp cap. Expression of factor eIF4E, elongation factor eEF2K, and tau v2 protein was assessed in siRNA-treated cells (Figure 3) .

Figure 3 Western blot of eIF4E, eEF2K, and tau v2 extracted from non-AD cells treated with eIF4E siRNA
Adapted from Veo BL, Krushel LA. Translation initiation of the human tau mRNA through an internal ribosomal entry site. J Alzheimers Dis. 2009; 16(2) :271-5.
-Recently fed ob/ob mice show deficient binding of glucagon to its G protein-coupled receptor, which most likely leads to:

Quizplus · Accepted Answer

11ecba2d_0f74_cbd6_a3bf_63091a795155_MD0008_00 Glucagon acts on target cells by binding its G protein-coupled receptor on the cell membrane and inducing the adenylyl cyclase/cAMP second messenger cascade. The G protein "attached" to the transmembrane cell surface receptor is composed of three subunits: alpha, beta, and gamma. When inactive, the alpha subunit (G_a) is bound to GDP, which is then replaced with GTP on ligand-receptor binding. The GTP-bound G_a dissociates from the beta and gamma subunits and proceeds to activate adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cAMP, a second messenger. cAMP then activates protein kinase A, which subsequently phosphorylates the proteins necessary to produce ligand-specific physiological effects (eg, glucagon: induction of glycogenolysis and gluconeogenesis). In the given scenario, the downstream effects of deficient glucagon binding in recently fed ob/ob mice would decrease the following: exchange of GDP for GTP; adenylate cyclase activity; conversion of ATP to cAMP; and protein kinase A activity. (Choices A and B) Deficient binding of glucagon to its G protein-coupled receptor would decrease adenylate cyclase activity, which would result in reduced conversion of ATP to cAMP (not cAMP to ATP). (Choice C) GDP deactivates the G_a subunit, but GTP activates the G_a subunit. Decreased glucagon binding to its G protein-coupled receptor would lead to decreased activation of the G_a subunit, so a decreased exchange of GDP (deactivating) for GTP (activating) would be observed. Educational objective: In the G protein-regulated cAMP signaling pathway, a ligand binds the transmembrane G protein-coupled receptor and activates the GDP-bound alpha subunit of the G protein by replacing GDP with GTP. The activated G alpha subunit activates the enzyme adenylyl cyclase, which catalyzes the conversion of ATP into cAMP. Elevated cAMP leads to the activation of protein kinase A and subsequent signaling effects.

Passage Alzheimer Disease (AD) Is a Progressive Condition Affecting Memory and and Cognition