br Concluding Remarks and Future Directions The

Concluding Remarks and Future Directions The physiological significance of autophagy in neuronal function is steadily emerging. The studies discussed herein reveal that key neuronal functions, such as neurotransmitter release, pruning of dendritic spines, and behavioural outputs of neural networks are all shown to depend to some extent on local regulation of autophagy. Future work should concentrate on working out the details, as autophagy is likely to have adapted different functions in different neuronal subpopulations and in different forms of plasticity. As protein turnover is known to be crucial for synaptic plasticity, the contribution of autophagy to these processes should be more directly examined, as well as its interaction with the proteasome, which is known to be modulated by neuronal activity and plasticity (see Outstanding Questions) 96, 97, 98. As an initial step towards understanding how the homeostasis of proteins, signalling lipids, nucleic acids, and organelles are dictated by autophagy, novel methods are needed to characterize the Fmoc-His(Boc)-OH.CHA mg and dynamic nature of the autophagic cargo during different neuronal processes. These include the isolation and purification of autophagosomes from different neuronal compartments to gain insight into cargo species, the distinction of secretory from degradative autophagosomes, and finally, the development of genetically encoded reporters for monitoring selective autophagy, such as mitophagy, in mammalian neurons, in vitro and in vivo.
Acknowledgements
Introduction Autophagy is a catabolic process in which cytoplasmic components, such as damaged organelles, proteins, lipids, or pathogens, are sequestered within double-membrane vesicles called autophagosomes (0.5–1.5μm diameter) and delivered to lysosomes for degradation and recycling (Fig. 1). While originally thought to be a bulk and nonselective process, it is now understood that autophagy regulates the selective degradation of pathogens (xenophagy) and organelles, including mitochondria (mitophagy), peroxisomes (pexophagy), endoplasmic reticulum (ER) (reticulophagy), and lipid droplets (lipophagy) (Galluzzi et al., 2017). The identification of over 30 conserved autophagy-related (ATG) genes has defined core sets of machinery for the five major steps of autophagy: initiation, nucleation, elongation, closure, and fusion (Fig. 1) (Feng et al., 2014, Mercer et al., 2018). Dysregulated autophagy is a hallmark of cancer (Hanahan & Weinberg, 2011), and thus, a frequent question is whether autophagy should be activated or inhibited for cancer therapy. Unfortunately, the answer to this question is complex and context-dependent as autophagy has paradoxical functions as both a tumor suppressor and tumor promoter and can serve to promote or suppress cell death (Levy, Towers, & Thorburn, 2017). During cancer development, autophagy constrains tumor initiation through the removal of dysfunctional organelles, such as mitochondria, and reactive oxygen species that drive genomic instability and malignant transformation (Yang et al., 2011). In contrast, autophagy supports cell survival in established tumors by providing an intracellular source of nutrients to meet the high proliferative and metabolic demands of the hostile, and often nutrient-deprived, tumor microenvironment (Galluzzi et al., 2015, Rebecca and Amaravadi, 2015, Zhi and Zhong, 2015). As high autophagic flux is associated with poor patient prognosis, enhanced metastasis, and resistance to chemotherapy (Lazova et al., 2012, Mikhaylova et al., 2012), inhibiting autophagy may be an effective anticancer strategy. Alternatively, autophagy can serve as a cell death mechanism to kill cancer cells that are resistant to canonical cell death signaling. Here, we will provide an overview of the major steps in mammalian autophagy, discuss the regulation of each step by sphingolipid metabolites, and describe the functions of sphingolipid-mediated autophagy in cancer.