Compartment‐specific dynamics and functions of autophagy in neurons

Abstract

Autophagy is a lysosomal degradation pathway that is critical to maintaining neuronal homeostasis and viability. Autophagy sequesters damaged and aged cellular components from the intracellular environment, and shuttles these diverse macromolecules to lysosomes for destruction. This active surveillance of the quality of the cytoplasm and organelles is essential in neurons to sustain their long-term functionality and viability. Indeed, defective autophagy is linked to neurodevelopmental abnormalities and neurodegeneration in mammals. Here, we review the mechanisms of autophagy in neurons and functional roles for autophagy in neuronal homeostasis. We focus on the compartment-specific dynamics of autophagy in neurons, and how autophagy might perform non-canonical functions critical for neurons. We suggest the existence of multiple populations of autophagosomes with compartment-specific functions important for neural activity and function. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 298-310, 2018.

Axonal Degeneration in AD: The Contribution of Aβ and Tau

“…Axons depend on the constant remodeling of damaged proteins and organelles to maintain their correct functioning and connectivity (Maday and Holzbaur, 2016). This remodeling depends on homeostatic/degradation systems such as the UPS and autophagy (Korhonen and Lindholm, 2004;Kulkarni and Maday, 2018). Acetylation of tau inhibits the degradation of phosphorylated tau by the UPS, and the accumulation of acetylated tau has been identified in AD brains (Min et al, 2010(Min et al, , 2015.…”

“…These observations suggest that autophagy impairment is associated with the deposition of pathological tau and contributes to neuronal demise in AD. Transport of autophagic vesicles loaded with unfolded proteins and organelles from distal axonal domains relies on a well-functioning retrograde transport to reach the soma, where autophagy degradation occurs (Maday and Holzbaur, 2014;Kulkarni and Maday, 2018). Dysregulations of tau observed in AD can impair dyneinretrograde axonal transport (Wang et al, 2015), which may lead to autophagy disruption and accumulation of autophagic vesicles within axons.…”

Dysfunction of Optineurin in Amyotrophic Lateral Sclerosis and Glaucoma

“…Neurons are post-mitotic; hence, they are particularly dependent on autophagy to dilute dysfunctional proteins and organelles. Thus, highly precise protein quality control systems are essential for the survival of neurons and their specialized morphologies require specific adaptations of autophagy, as well as other cellular processes ( 111 , 112 ).…”

The Virtuous Cycle of Axon Growth: Axonal Transport of Growth‐Promoting Machinery as an Intrinsic Determinant of Axon Regeneration

“…Neuronal autophagy is well studied (Jin et al, ), largely because its misregulation is implicated in degenerative diseases such as Alzheimer's, Parkinson's, and Huntingdon's disease as well as amyotrophic lateral sclerosis (ALS)/motor neuron disease (Dikic and Elazar, ). There are a number of excellent recent reviews which comprehensively discuss the function and regulation of autophagy within neurons (Kulkarni et al, ; Kulkarni and Maday, ; Nikoletopoulou and Tavernarakis, ; Stavoe and Holzbaur, ). Here we discuss the involvement of autophagy in the process of axon growth and regeneration, the presence of autophagy specifically within the axon, how autophagic mechanisms may vary between neuronal types of differing regenerative ability, and the regulation/interaction of Rab11 and recycling endosomes with the autophagosome.…”