Local mRNA translation in growing axons allows for rapid and precise regulation of protein expression in response to extrinsic stimuli. However, the role of local translation in mature CNS axons is unknown. Such a mechanism requires the presence of translational machinery and associated mRNAs in circuit-integrated brain axons. Here we use a combination of genetic, quantitative imaging and super-resolution microscopy approaches to show that mature axons in the mammalian brain contain ribosomes, the translational regulator FMRP and a subset of FMRP mRNA targets. This axonal translational machinery is associated with Fragile X granules (FXGs), which are restricted to axons in a stereotyped subset of brain circuits. FXGs and associated axonal translational machinery are present in hippocampus in humans as old as 57 years. This FXGassociated axonal translational machinery is present in adult rats, even when adult neurogenesis is blocked. In contrast, in mouse this machinery is only observed in juvenile hippocampal axons. This differential developmental expression was specific to the hippocampus, as both mice and rats exhibit FXGs in mature axons in the adult olfactory system. Experiments in Fmr1 null mice show that FMRP regulates axonal protein expression but is not required for axonal transport of ribosomes or its target mRNAs. Axonal translational machinery is thus a feature of adult CNS neurons. Regulation of this machinery by FMRP could support complex behaviours in humans throughout life.
• Binding to fibrinogen is mediated by the central region of Ab42 and is enhanced by its C-terminal residues.• Ab42 binds the aC region of fibrinogen, delaying plasminmediated fibrin cleavage and generating a persistent aC degradation product.The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with b-amyloid (Ab), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Ab-fibrinogen interaction. We identified the central region of Ab42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Ab and by naturally occurring p3 peptides, Ab17-40 and Ab17-42. X-ray crystallographic analysis revealed that Ab42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen b-chain (b384-393). Furthermore, we identified an additional Ab-binding site within the aC region of fibrinogen. Ab binding to this aC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Ab-fibrinogen interaction and clarifies the mechanism by which Ab-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Ab-fibrinogen interaction to treat cerebrovascular abnormalities in
The ability of the nervous system to convert transient experiences into long-lasting structural changes at the synapse relies upon protein synthesis. It has become increasingly clear that a critical subset of this synthesis occurs within the synaptic compartment. While this process has been extensively characterized in the postsynaptic compartment, the contribution of local translation to presynaptic function remains largely unexplored. However, recent evidence highlights the potential importance of translation within the presynaptic compartment. Work in cultured neurons has shown that presynaptic translation occurs specifically at synapses undergoing long-term plasticity and may contribute to the maintenance of nascent synapses. Studies from our laboratory have demonstrated that Fragile X proteins, which regulate mRNA localization and translation, are expressed at the presynaptic apparatus. Further, mRNAs encoding presynaptic proteins traffic into axons. Here we discuss recent advances in the study of presynaptic translation as well as the challenges confronting the field. Understanding the regulation of presynaptic function by local protein synthesis promises to shed new light on activity-dependent modification of synaptic architecture.
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