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They discover the mechanism that ensures the reserve of stem cells for neuronal generation in adulthood

The results of the study point to the impact on future treatments of neurodegenerative diseases.

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They discover the mechanism that ensures the reserve of stem cells for neuronal generation in adulthood

The results of the study point to the impact on future treatments of neurodegenerative diseases


A research group from the Institute of Biomedicine of Valencia (IBV), of the Higher Council for Scientific Research (CSIC), has discovered that autophagy, a cellular recycling mechanism, is what allows neural stem cells to enter into rest after first week of life, becoming part of the reserve necessary for the formation of neurons in adulthood.

The results are published in the journal 'Nature Communications' and represent "an advance in the understanding of brain development, with an impact on future treatments of neurodegenerative diseases."

From the CSIC they explain that the human brain constantly generates new neurons, even during adulthood. To do this, it has reserves of neural stem cells, which are at rest after their proliferation during brain formation. Now,

At the time of Santiago Ramón y Cajal, the Spanish Nobel Prize winner in the study of the brain, it was thought that there was no neuronal generation in the adult brain. However, in the last 30 years it has been shown that, in certain regions of the brain such as the hippocampus, there are reserves of neural stem cells capable of producing new neurons throughout life. In the adult stage, these stem cells are in a resting, 'sleeping' state, but they can be recruited (awakened) to form fully functional neurons.

Neural stem cells in the adult mammalian brain are derived from actively dividing precursors, which leave their highly proliferative state to form dormant reservoirs during development.

"Until now, it was unknown how these reservoirs are established. In this work we reveal for the first time an intrinsic mechanism of the neural stem cells themselves necessary to go, en masse, from the proliferative state to the resting state characteristic of the adult," he says. in a statement, Helena Mira Aparicio, CSIC scientist at the IBV who leads the study.

His Stem Cells and Aging team at the IBV had already identified the external signals that control the balance between rest and activity of stem cells in adulthood. "We now show that the first entry of stem cells into the quiescent state during the early postnatal phase is regulated by a different cellular process, called autophagy," reveals Mira. "Autophagy is a recycling mechanism involved in eliminating damaged components, such as protein aggregates, to safeguard cellular integrity. If this process fails, stem cells are incapable of entering into rest," points out the Castellón scientist.

The study was carried out using transgenic animals with stem cells deficient in Atg7, a key gene for autophagy. They have also used cultures of stem cells isolated from the hippocampus of mice and manipulated with small molecules that activate or inhibit autophagy.

"When stem cells go to rest, protein aggregates accumulate and there is an increase in the autophagic machinery to recycle these aggregates. If this process is interfered with, the cells continue to divide," describes the CSIC researcher. "Once they acquire a resting state, they need autophagy to function correctly to remain inactive and not exhaust themselves prematurely. Therefore, autophagy controls the conversion of precursor cells of neurodevelopment into stem cells characteristic of adults," concludes Mira.

In addition to delving into the basic knowledge about neurodevelopment, "the identification of autophagy as a mechanism capable of controlling the entry and exit of the resting state of neural stem cells may have implications in aging," declares the CSIC researcher.

One of the lines of study of his group at the Institute of Biomedicine of Valencia explores how to recruit stem cells from the aging brain to produce new neurons, and thus improve the structural plasticity and functionality of the brain.

"During aging, and in age-related neurodegenerative diseases such as Alzheimer's, there is a lower production of hippocampal granule neurons. We know that this is due to the fact that neural stem cells decrease in number and are also increasingly deeply 'asleep.' "We have seen in the cellular models with which we work that pharmacological and genetic modulation of autophagy is sufficient to 'wake up' stem cells, an encouraging result," describes Mira.

Thus, "the activation of endogenous stem cell reserves to promote the controlled production of new neurons and their integration into neural circuits may be a means of intervention to alleviate some effects associated with brain aging, both healthy and pathological," the researcher advances. of the CSIC.