Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Abstract

Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association.

Developing Novel Experimental Models of m-TORopathic Epilepsy and Related Neuropathologies: Translational Insights from Zebrafish

“…Aberrant mTOR signaling is also strongly linked to neurodevelopmental and neurodegenerative diseases [ 34 ]. For instance, TSC, neurofibromatosis type 1 (NF1) and fragile X syndrome are all caused by mutations of mTOR-inhibiting genes ( Table 1 ) [ 35 ], whereas rapamycin-induced mTOR inhibition prevents the proliferation of cytomegalic neurons and reduces episodic convulsions [ 36 ].…”

The ESCRT Machinery: Remodeling, Repairing, and Sealing Membranes

“…Autophagy is a critical cellular process by which cytosolic components, from macromolecules to cellular organelles, are degraded in a controlled manner inside lysosomes [80]. This is essential for maintaining cell homeostasis and ensuring cell survival, allowing the removal of potentially harmful protein aggregates or damaged organelles.…”

“…The process starts with a double-membrane structure termed the phagophore that encloses bulk cytoplasm or specific cargo. The phagophore membrane, which is thought to come from different sources like the endoplasmic reticulum or the plasma membrane, eventually closes to form a complete autophagosome, resulting in engulfment of the cargo [80]. Then, the autophagosome fuses with a lysosome and the sequestered cargo is degraded by lysosomal hydrolases.…”

Presynaptic Autophagy and the Connection With Neurotransmission

“…This is particularly important because most neurons are not regenerated during adult life and they need to maintain functional over many decades. Furthermore, autophagy also serves a more direct role in neuronal physiology, like neurotransmission ( Kuijpers et al, 2021 ), synaptic plasticity ( Compans et al, 2021 ; Pan et al, 2021 ), circuit development ( Tang et al, 2014 ; Linda et al, 2021 ; Zapata-Muñoz et al, 2021 ) and survival ( Hara et al, 2006 ; Komatsu et al, 2006 ; Komatsu et al, 2007 ). Moreover, the spatial organization of autophagy within neurons is unique.…”