Neuronal Autophagy: Regulations and Implications in Health and Disease

Abstract

Autophagy is a major degradative pathway that plays a key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed in a double-membrane autophagosome that fuses with lysosomes, is orchestrated by a complex cascade of events. Autophagy has a particularly strong impact on the nervous system, and mutations in core components cause numerous neurological diseases. We first review the regulation of autophagy, from autophagosome biogenesis to lysosomal degradation and associated neurodevelopmental/neurodegenerative disorders. We then describe how this process is specifically regulated in the axon and in the somatodendritic compartment and how it is altered in diseases. In particular, we present the neuronal specificities of autophagy, with the spatial control of autophagosome biogenesis, the close relationship of maturation with axonal transport, and the regulation by synaptic activity. Finally, we discuss the physiological functions of autophagy in the nervous system, during development and in adulthood.

Keywords: autophagy; compartmentalisation; neurodegeneration; neurodevelopment; regulations.

Figure 1

Schematic representation of the autophagic pathway. This process produces a double-membrane vesicle called an autophagosome. During its elongation, the autophagosome recognises and engulfs old cytoplasmic (organelles, proteins, etc.) and damaged material (organelles, proteins aggregates, etc.). After maturation, the intravesicular content is degraded due to the fusion with lysosomes and is re-used by the cells to produce new proteins and organelles. Autophagy is regulated by the autophagy-related (ATG) proteins and many other regulators. Core autophagy proteins mutated in neuronal pathologies are tagged by a red asterisk and are described in more detail in Table 1. OPTN: Optineurin; NBR1: Next to BRCA1 gene 1 protein; ESCRT: endosomal sorting complexes required for transport; CHMP: charged multivesicular body protein; HOPS: homotypic fusion and protein sorting complex; EPG5: ectopic P granules protein 5 homolog; VAMP8: vesicle-associated membrane protein 8; STX17: syntaxin 17; and SNAP29: synaptosomal-associated protein 29.

Figure 2

Schematic representation of the dynamics of neuronal autophagy. (A) Autophagosome (blue) biogenesis takes place in the distal part of the axon. (B) After their formation, autophagosomes first undergo bidirectional movement and switch to retrograde transport to move towards the soma along microtubules with the help of motor proteins (dynein and kinesin). During this transport, autophagic vesicles (AVs) mature by fusing with endosome (green) and/or lysosome (red) to generate, respectively, amphisome (yellow) and/or autolysosome (orange). In the proximity of the soma, AVs become more mature and exhibit bidirectional movement. (C) Dendritic autophagosome biogenesis is regulated by synaptic activity. Depolarisation, induced by KCl or through AMPAR/NMDAR, increases the density of AVs in dendrites and decreases displacement. Lysosomes from the soma are also recruited to dendrites after depolarisation. In somal autophagy, AVs tend to be less mobile than in axons or dendrites. This compartment is the main site of final autolysosome content degradation. Ca: calcium; EndoA: endophilin A; JIP: JNK-interacting protein; Htt: Huntingtin; HAP1: Huntingtin-associated protein 1; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; and NMDA: N-methyl-D-aspartate.

Figure 3

Roles of autophagy in neuronal physio(patho)logy. The autophagic process is fundamental for neuronal homeostasis and is implicated in stem cell proliferation and differentiation, neural migration, neurite outgrowth, and synapse development and plasticity. Mutation of proteins involved in autophagy pathway regulation leads to neurodevelopmental diseases. FMCD: Focal malformations of cortical development; NDD: Neurodevelopmental disorder; CP: Cerebral palsy; HSP: Hereditary spastic paraplegia; NBIA: Neurodegeneration with brain iron accumulation; ASD: Autism spectrum disorder; SZ: Schizophrenia; BD: Bipolar disorders; RNF216: Ring Finger Protein 216; Mir505-3p: miRNA 505-3p; and Tsc: tuberous sclerosis protein.

Figure 4

Role of autophagy in synapse homeostasis. In pre- or post-synaptic compartments, autophagy has a key role in regulating synaptic proteins or vesicles and is implicated in synaptic plasticity in response to environmental stimulation. Disruption in the autophagic process leads to accumulation of intracellular components, neurotransmitter receptors, and membrane-associated proteins in pre- or post-synaptic compartments, leading to an enlargement of the pre-synaptic compartment and alterations in neurotransmission. OA: Overactivation; GABA_AR: gamma-aminobutyric acid receptor; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; and NMDAR: N-methyl-D-aspartate receptor.