In a paper published on March 15, 2018, in the journal Science, Stanford researchers led by Dr. Dena Leeman showed that intracellular protein aggregates accumulate within the lysosomes of neural stem cells that were previously thought not to suffer from this problem [1].

Intracellular waste disposal 101

Dysfunctional proteins and organelles within a cell constitute intracellular waste that the cell needs to dispose of. To do so, the cell may avail itself of proteasomes and lysosomes. Proteasomes are protein complexes that, with the help of enzymes, break down other, unnecessary proteins into shorter amino acids that can then be recycled to build new, useful proteins. Proteasomes are found within the cell nucleus and in the cytosol—the aqueous solution in which everything in a cell floats. The discovery of proteasomes happened later than that of lysosomes, which, for a while, were thought to be the only cellular waste management systems.

Lysosomes can be thought of as recycling facilities—acidic vesicles containing a number of different enzymes, each of which catalyzes a different reaction needed to break down a specific type of waste. Thanks to their arsenal of chemicals, lysosomes can break down nearly all kinds of garbage they come across—but when they fail to recycle some of the trash, things can get ugly.

If the lysosome cannot break down a certain type of protein, that protein will tend to accumulate in it, gradually making it more and more dysfunctional and unable to process other types of proteins that it would normally be able to deal with. Over time, as an increasing number of lysosomes within the same cell begin to malfunction, the cell becomes unable to get rid of unwanted proteins that impair its functioning, and just like a city with a really inefficient waste management system, it will end up drowning in its own trash.







Expect the unexpected

Lysosomal dysfunction is a well-known phenomenon, both as a hallmark of aging and the cause of rare, inherited metabolic disorders called lysosomal storage diseases. As we age, deposits of unbreakable protein types accumulate within the lysosomes of cells in all sorts of tissues, but, up until recently, it was believed that this didn’t happen in the case of quiescent neural stem cells (qNSCs).

Neural stem cells are multipotent stem cells capable of turning into different types of brain tissue cells. When they are quiescent, they just sit around in their tissue waiting to be activated, and when this happens, they start dividing to make new neurons. In their study, the authors of the Science paper presented their findings on the differences they observed in how quiescent and activated neural stem cells (aNSC) in mice maintain proteostasis, and their results were rather surprising.

What the study found

The researchers proceeded by collecting both quiescent and activated neural stem cells from both old and young mice. The gene expression profile of these cells revealed that aNSC expressed more proteasome-associated genes, whereas qNSCs expressed more lysosome-associated genes; it was also observed that qNSCs had more and larger lysosomes than their activated counterparts. Overall, these results made the researchers conclude that the two cell types rely predominantly on different parts of the cellular waste management system.







When the researchers stained both qNSCs and aNSCs with a fluorescent dye that binds to protein aggregates, they noted that the quiescent stem cells were brighter than activated ones; rather paradoxically, this means that qNSCs contain more protein aggregates than aNSCs, even though non-dividing quiescent stem cells produce much fewer proteins in the first place; in fact, the researchers didn’t expect to find many protein aggregates at all in qNSCs and yet they had far more than aNSCs did. Furthermore, a large proportion of the aggregates in qNSCs was contained in their lysosomes, which appeared to be rather slow at digesting their contents despite possessing the right level of acidity required to carry out their job. This, in turn, means that the aggregates tend to accumulate within qNSC lysosomes.

These results were observed in cells coming from both old and young mice. The accumulation of aggregates in young qNSCs—which, in principle, should just be resting and do not do much else until they are eventually activated—led the researchers to suspect that aggregates might have a biological function in these young cells, such as being a source of energy or nutrients when they are finally digested.

While the accumulation of aggregates was observed both in old and young qNSCs, the situation was predictably worse in older ones, which expressed fewer lysosome-associated genes than their younger counterparts and thus presented even higher levels of insoluble aggregates. The accumulation of these indigestible protein clumps in the brain has long been associated with neurodegenerative diseases, such as Alzheimer’s, and on top of that, it impairs neurogenesis—the ability of the brain to form new neurons—by making it harder for qNSCs to activate and become aNSCs that can then differentiate into whatever neuron type is needed.

The good news is that Dr. Leeman’s team was able to artificially clear old qNSCs of excess protein aggregates, either by enhancing their lysosomal activity or by limiting their nutrition intake to put a brake on how much protein they could produce. The researchers observed that cleared qNSCs were more readily turned into aNSCs upon being exposed to growth factors (i.e., substances the body naturally uses to stimulate cellular growth). Thus, in their paper, the researchers suggested that these techniques might prove useful for activating elderly qNSCs in vivo.

Conclusion







This study seems to provide yet more evidence in support of the view of aging as a chronic damage accumulation process that might be ameliorated, or perhaps even reversed, if only appropriate maintenance and repair interventions are devised and implemented. As always, before a definitive answer can be given, more research is needed—in this particular case, to figure out why qNSCs and aNSCs prefer different recycling methods, among other things—but this study is another of many that seem to suggest we’re on the right track to understanding and defeating aging.

Literature

[1] Leeman, D. S., Hebestreit, K., Ruetz, T., Webb, A. E., McKay, A., Pollina, E. A., … & Mahmoudi, S. (2018). Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science, 359(6381), 1277-1283.