Enhanced Proteasomal Activity Restores Declining Self-Renewal in Aging Neural Stem Cells

The proteasome is a type of cellular structure tasked with breaking down damaged and unwanted proteins, its activities one part of a broad variety of maintenance mechanisms found inside the living cell. Today I'll point out the latest of a number of studies from recent years to investigate the underlying reasons for associations between declining cellular maintenance and specific aspects of degenerative aging. The researchers noted here have linked proteasomal activity to the vitality of neural stem cells. They show that both decline in aging, but the stem cells can be restored to more youthful vigor when proteasomes are artificially induced to pick up the slack once more.

Stem cells maintain tissues by providing a source of new cells and signals that influence cellular behavior. Even in the brain, stem cell populations deliver a supply of new neurons over time, and this is one of the sources of neural plasticity, the ability of the brain to change, learn, adapt, and (to a limited degree) repair itself. The activity of stem cell populations declines with advancing age, however, most likely a reaction to rising levels of cell and tissue damage. Less activity serves to reduce the risk of death by cancer, but at the cost of a faster decline into frailty and organ failure, the result of failing tissue maintenance. In the brain, this means a progressive loss of neural plasticity, and this is thought to contribute meaningfully to the development of neurodegenerative conditions. It probably has subtle and profound effects on the state of the human mind as well, beyond those caused by obvious structural failures in brain tissue, though that is far harder to prove one way or another.

As is the case for stem cell activity, proteasomal activity is also known to decrease in older tissues. All mechanisms of cellular maintenance go the same way, unfortunately, and this is a recurring theme in aging research. There are many who view aging as at least in part a garbage catastrophe: a downward spiral led by broken mechanisms and a growing inability to keep up. Many models of enhanced longevity have greater maintenance activities than their less fortunate peers. Naked mole rats for example, have very effective proteasomes. Aging is the accumulation of cell and tissue damage, and even repair systems get damaged - though in likelihood these age-related declines are not the direct results of damage, but rather mediated by a complex web of interacting signals and protein levels. For much of the past decade, some researchers have looked towards boosted maintenance, including increased proteasomal activity, as a possible way to slow the onset of aging or treat degenerative conditions. Despite a lot of research and many published papers, little concrete progress towards clinical translation of research has occurred on this front, however.

Essential role of proteasomes in maintaining self-renewal in neural progenitor cells

The breakdown of protein homeostasis has been suggested to be tightly associated with the aging process, because all cells have to keep a dynamic balance between protein synthesis and degradation in order to maintain their integrity and normal functions. In fast-proliferating cells, it is particularly crucial to recycle obsolete macromolecules to provide the raw materials for synthesis of subcellular compartments and molecules to satisfy the requirement of rapid proliferation and/or differentiation. Such a self-renewal ability of cells, however, is gradually compromised and eventually diminished with age. Hallmarks of aged cells include increased accumulation of hyper-oxidative, misfolded, or abnormally-aggregated proteins, all of which result from the dysfunctional cell clearance mechanisms, especially the protein degradation pathway.

The proteasome-dependent degradation is one of such cellular clearance mechanisms for retaining intracellular protein homeostasis, which targets and subsequently degrades damaged, misfolded or redundant proteins. The dysfunction of proteasomes, in turn, may contribute to the occurrence of many aging-related diseases. Various studies have shown that proteasomal activity might be compromised during the aging process in both animals and cells, given that its decrease has been found in a variety of aged tissues in humans, non-human mammals, and even in lower organisms such as fruit flies.

In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through both in vivo and in vitro analyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. We previously increased proteasomal activity in bone marrow stem cells by exogenously applying the proteasome activator 18α-GA or genetically over-expressing the β-subunit PSMB5, and found that both methods could effectively improve cell integrity and ameliorate replicative senescence, in addition to enhancements of cell survival and neuronal differentiation following the brain transplantation of PSMB5-overexpressing bone marrow stem cells. In the current study, we observed similar effects of 18α-GA on NPCs.

Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs both in vitro and in vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases.

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