Axonal autophagy: Mini-review for autophagy in the CNS

Abstract

Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the distal axon occurs via a conserved pathway that is required to maintain functional synapses and prevent axon degeneration. Autophagosomes are formed de novo at the axon terminal in a stepwise assembly process, engulfing mitochondrial fragments, aggregated proteins, and bulk cytosol in what appears to be a nonselective uptake mechanism. Following formation, autophagosomes fuse with late endosomes/lysosomes and then are rapidly and efficiently transported along the axon toward the soma, driven by the microtubule motor cytoplasmic dynein. Motile autophagosomes mature to autolysosomes in transit by fusing with additional late endosomes/lysosomes, arriving at the soma as fully competent degradative organelles. Misregulation of neuronal autophagy leads to axonal degeneration and synaptic destabilization, and has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.

Keywords: Autophagosome biogenesis; Axon degeneration; Macroautophagy; Mitophagy; Neuronal homeostasis.

Figure 1. Autophagosomes are formed constitutively in the distal axon and are actively trafficked toward the soma by the microtubule motors cytoplasmic dynein and kinesin

A. Autophagosome biogenesis at the axon terminal is a stepwise pathway, starting from an omegasome on the ER, that grows to form a double-membrane phagophore that engulfs cargos including aggregated proteins and mitochondrial fragments, finally sealing to form a spherical compartment marked by LC3B that sequesters its cargos from the cytosol for subsequent degradation. B. Once formed at the axon terminal, autophagosomes bind to microtubules via associated dynein and kinesin motors. As autophagosomes move along the axon, they fuse with late endosomes/lysosomes and gradually acidify to form a fully competent degradative organelle, termed the autophagolysosome. C. Super-resolution micrograph of a DRG neuron (2DIV) showing the interaction of GFP-LC3B-labeled autophagosomes with microtubules at the axon terminal. GFP-LC3B was stained with an anti-GFP-488 nanobody (Chromtek) and microtubules were stained with an antibody to tyrosinated tubulin (Millipore). Scale bar, 5 μm.