RESUMEN
Hermansky-Pudlak syndrome (HPS) is an inherited disorder of intracellular vesicle trafficking affecting the function of lysosome-related organelles (LROs). At least 11 genes underlie the disease, encoding four protein complexes, of which biogenesis of lysosome-related organelles complex-2 (BLOC-2) is the last whose molecular action is unknown. We find that the unicellular eukaryote Dictyostelium unexpectedly contains a complete BLOC-2, comprising orthologs of the mammalian subunits HPS3, -5, and -6, and a fourth subunit, an ortholog of the Drosophila LRO-biogenesis gene, Claret. Lysosomes from Dictyostelium BLOC-2 mutants fail to mature, similar to LROs from HPS patients, but for all endolysosomes rather than a specialized subset. They also strongly resemble lysosomes from WASH mutants. Dictyostelium BLOC-2 localizes to the same compartments as WASH, and in BLOC-2 mutants, WASH is inefficiently recruited, accounting for their impaired lysosomal maturation. BLOC-2 is recruited to endolysosomes via its HPS3 subunit. Structural modeling suggests that all four subunits are proto-coatomer proteins, with important implications for BLOC-2's molecular function. The discovery of Dictyostelium BLOC-2 permits identification of orthologs throughout eukaryotes. BLOC-2 and lysosome-related organelles, therefore, pre-date the evolution of Metazoa and have broader and more conserved functions than previously thought.
Asunto(s)
Dictyostelium , Lisosomas , Proteínas Protozoarias , Dictyostelium/genética , Dictyostelium/metabolismo , Lisosomas/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Animales , Evolución Molecular , Proteína Coatómero/genética , Proteína Coatómero/metabolismo , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/metabolismoRESUMEN
Neurocognitive dysfunction after cardiac surgery can present with diverse clinical phenotypes, which include postoperative delirium, postoperative cognitive dysfunction, and stroke, and it presents a significant healthcare burden for both patients and providers. Neurologic monitoring during cardiac surgery includes several modalities assessing cerebral perfusion and oxygenation (near-infrared spectroscopy, transcranial Doppler and jugular venous bulb saturation monitoring) and those that measure cerebral function (processed and unprocessed electroencephalogram), reflecting an absence of a single, definitive neuromonitor. This narrative review briefly describes the technologic basis of these neuromonitoring modalities, before exploring their use in clinical practice, both as tools to predict neurocognitive dysfunction, and with a bundle of interventions designed to optimize cerebral oxygen supply, with the aim of reducing postoperative delirium and cognitive dysfunction following cardiac surgery.