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br Autophagy in the central nervous system The autophagic
Autophagy in the central nervous system
The autophagic process appears to be very important for the cells of the central nervous system, as it allows to maintain the functional integrity of the nervous tissue. Indeed macroautophagy is involved in the regulation of homeostasis of the CNS, playing an important role in the removal of degraded elements within the neuron. In particular, Maday and Holzbaur (2014) have reported that under basal conditions, autophagosomes are continuously generated in the axon tip. Inhibition of autophagy may produce neurodegeneration in mature neurons, because neuronal homeostasis is altered (Hara et al., 2006).
Neurons are non dividing cells, they are more sensitive to accumulation of toxic substances and they require a high energy to perform their functions. For this reason, they have need to degrade the faulty cytoplasmic components to preserve their survival and maintenance of specialized functions (Lee, 2012). Moreover, neurons have specialized structures for intercellular communication (axons, dendrites and synapses) that permit transport of proteins, organelles and autophagosomes. Defects in autophagic pathways affect the intercellular communication due to the accumulation of faulty protein Fmoc-Asp-OAll sale and damaged organelles, and contribute to neurotoxicity (Shi et al., 2012).
During embryonic development and in the fully developed organism, autophagy allows to determine and to maintain the correct shape and function of neuronal cells (Orrenius et al., 2013). Mizushima and Levine (2010) have reported that the autophagy has a role in several stages of embryogenesis of mammalian, and it is particularly important in the pre-implantation period and in the early postnatal period. Indeed, the deletion of some ATG genes leads to death during mid-embryonic development and to developmental abnormalities in the postnatal period.
The activation of autophagy, hence, may have a therapeutic benefit, to reduce cell death and to protect the health of the organism (Srivastava et al., 2016). As autophagy may be considered a balance between autophagosome formation and autophagic degradation, an impairment in this process can induce the onset of pathological changes. However, Nikoletopoulou et al. (2015) have reported that different subtypes of neurons are differentially vulnerable to the autophagic flux, because they exhibit different dependence on the autophagic mechanism.
Autophagy and environmental neurotoxicants
Conclusions
Autophagy is an essential process for maintaining cellular homeostasis, allowing cell survival and adaptation to environmental stress (Cuervo, 2004, Rodolfo et al., 2016). In particular, the autophagic process is fundamental for the cells of the central nervous system, because it allows to maintain the functional integrity of the nervous tissue. Indeed, neurons are particularly sensitive to autophagic processes, because as cells that do not divide, they are more sensitive than others to the accumulation of contaminants (Srivastava et al., 2016). Through the formation of autophagosomes, autophagy removes the degraded organelles within the neuron, allowing it to maintain the correct shape and function (Orrenius et al., 2013).
Livingstone (2001) showed that contaminant exposure generally induce oxidative stress that damage the protein and cell organelles. An excessive production/accumulation of ROS may alter cellular homeostasis, inducing mitochondrial dysfunction. However, during this process, autophagy is induced by ROS, as a compensatory mechanism to reduce oxidative damages, engulfing and degradating faulty organelles (Li et al., 2015a). Moreover, the possibility to up-regulate the autophagic process permits to remove degradated cellular constituents and conserve cell function (Cuervo, 2004). Therefore, autophagy may act as a friend, helping stressed neurons and maintaining cellular homeostasis.
Despite being considered a cytoprotective mechanism, autophagy is interlinked in terms of pathways, sub-cellular sites and organelles with apoptosis, while maintaining its own mechanisms (Nikoletopoulou et al., 2013, Berghe et al., 2015, Srivastava et al., 2016). Indeed, an impairment in any step of the autophagic pathway or an abnormally increased autophagic activity may lead to loss of neuronal homeostasis, inducing apoptosis (Hara et al., 2006, Shi et al., 2012, Cuervo and Wong, 2014, Giordano et al., 2014, Rubinsztein et al., 2015). Autophagy and apoptosis can coexist in the same cell types as death mechanism, but cells may progress towards autophagic cell death only when pro-apoptotic molecules are not activated (Cuervo, 2004, Puyal et al., 2012).