Alex K Chen Posted December 30, 2023 Report Share Posted December 30, 2023 Eg Quote GPLD1 is also exciting to Rich because in another part of his lab, a guy named Gonzalo Garcia was looking at differential mRNA translation, and he had discovered that all slow-aging mice have a lot of cap-independent translation That is they can pick a subset of the messenger RNAs and translate them in a special way, and cause proteins to be made in ways that are independent of the amount of RNA for that protein We’ve published now that GPLD1 is one of those proteins It is controlled not by changes in the transcription of the DNA into the RNA, but by the differential translation of the RNA into protein, in a cap-independent translation module This is our first serious link between the molecular biology of protein translation (Gonzalo’s stuff) and the physiological effects like cognition and BDNF (which was Xinna’s domain) on memory: cap-dependent initiation inhibitor 4EGI-1. We found that 4EGI-1 depleted polyribosomes in dendritic shafts and selectively prevented their upregulation in spine heads, but not bases and necks, during consolidation. Cap-independent upregulation was specific to spines with small, astrocyte-associated synapses. Our results reveal that cap-dependent initiation https://www.jneurosci.org/content/37/7/1862 "4EGI-1 reduces baseline polyribosomes in dendrites and prevents their upregulation after learning. Although translation is primarily cap dependent in eukaryotic cells, both IRES-mediated initiation and reactivation of stalled polyribosomes can occur in dendrites (Sutton and Schuman, 2005; Richter and Coller, 2015). It is conceivable that cap-independent translation predominates in dendrites during consolidation, or even under baseline conditions. If this is the case, 4EGI-1 should have no effect on polyribosomes in LA dendrites, and we therefore began by quantifying them" Many of the CIT mechanisms involve specific elongation and initiation factors in addition to proteins that recognize sequences or modifications in the sequence of 5′UTR, including 6- methyl- adenosine residues Treatments with ACA (starting early, i.e., at 6 months, or late, i.e., at 16 months) or Rapa (early or late) can significantly increase MGMT, NDRG1, and TFAM to levels equal to or higher than levels seen in young mice. In addition, ACA and Rapa (starting at either age) can also significantly increase Hsp70 above the levels seen in old control mice. In males, 17aE2 also increases all four of these CIT proteins, similar to the effects of ACA and Rapa. In contrast, females show no effects of 17aE2 on NDRG1, TFAM, or Hsp70. MGMT was upregulated in 17aE2- treated females, but only if mice were exposed from an early age (Figure 1c). The sex- specific effects of 17aE2 are in accord with similar sexual dimorphism for lifespan and a range of age- sensitive physiological endpoints (Garratt et al., 2017; Harrison et al., 2014). Analysis in kidneys showed a similar pattern (Figure 2 and Table S1), with age- related declines in the expression of CIT targets MGMT, NDRG1,and TFAM but not in Hsp70. ACA and Rapa, started early or late, significantly increased levels of MGMT, NDRG1, TFAM, Quote Link to comment Share on other sites More sharing options...
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