Abstract
As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.
Highlights
Among the many changes that occur with age, one of the most feared is the loss of cognitive abilities
We show that age-associated down-regulation of the cholesterol transport protein NPC1 may operate as double-faced, gain-loss, mechanism
Different studies have demonstrated that the loss of function of NPC1, either by mutations or by reduction in its levels, leads to the accumulation of cholesterol in organelles of the endo-lysosomal pathway resulting in functional alterations, the pathogenic agent in NPC1 seems to be the accumulation of the ganglioside GM2 (Zervas et al, 2001)
Summary
Among the many changes that occur with age, one of the most feared is the loss of cognitive abilities. Among the derangements in molecular processes, those related to proteostasis are gaining momentum (Hipp et al, 2019). Deficits in proteostasis encompasses defects in the process responsible for the biogenesis, folding, trafficking and degradation of proteins and membranes, resulting in the accumulation of misfolded and/or aggregated proteins in lysosomes and phagosomes. The defects in proteostasis with age are of multifactorial origin, including changes in the expression of genes related to folding and degradation, alterations in endocytic sorting and accumulation of oxidized proteins, inherently resistant to degradation (Mattson & Arumugam, 2018; Levy et al, 2019). Dysfunctional proteostasis may impair cellular function through several mechanisms, such as increased generation and release to the cytosol of oxidative products that will affect, among others, key synaptic structural and functional proteins, or by triggering changes which impede proper organelle interactions (e.g., lysosome-ER)
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