Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α

Abstract

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuitindependent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.adult neurogenesis | DNAJC5 | adult-onset neuronal ceroid lipofuscinosis | synaptic neurodegeneration | lysosome

The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies

“…At the same time, a persistent hyper-proliferation induced by mTOR hyper-activation may lead to the exhaustion of the NSCs pool. Such an effect can be reverted by the administration of the gold-standard mTOR inhibitor rapamycin [104]. Remarkably, the hyper-activation of mTOR signaling in transgenic mice results in a marked expansion of the SVZ stem cell compartment and subsequent glioma development [105].…”

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

“…In a recent study by Nieto-González et al, CSPα function has been linked to the mTOR signaling pathway. In this study, the authors found a hyperactivation of the mTOR pathway causing hyperproliferation of neurospheres generated from CSPa-deficient mice, although the precise mechanism by which this occurs is not yet resolved [185]. mTOR signaling is highly connected to lysosomal metabolism being influenced by lysosomal signals and negatively regulating autophagy [107,109].…”

Sestrins regulate age-induced deterioration of muscle stem cell homeostasis

“…A focal point of metabolic signaling is the nutrientsensitive protein complex mTORC1, which balances protein biosynthesis and autophagy to meet anabolic demands 33 . Regulation of mTORC1 34 is essential to prevent stem cell over-activation 35 and maintain quiescence 36 and loss of mTORC1 inhibition results in depletion of hematopoietic stem cells 37 . Sestrins are a unique class of metabolic regulators that titrate mTORC1 signaling and act as oxidative stress sensors, but their roles in adult stem cells has yet to be evaluated.…”

“…Integrating our data suggest Sestrins are important regulators of MuSC metabolism and the quiescent state. Several studies have shown that hyperactivation of mTORC1 results in stem cell loss 34,36 and interruptions to the maintenance of quiescence but none have yet demonstrated this behavior through Sestrins. Accordingly, Sestrin-dependent changes may be strong targets for…”