Mechanisms of neuronal homeostasis: Autophagy in the axon

• Autophagy is an essential lysosomal degradation pathway in neurons.
• Autophagosome biogenesis and maturation is spatiotemporally regulated in the axon.
• Autophagy maintains axonal homeostasis and regulates presynaptic function.
• Neuronal autophagy is altered in axonopathies and neurodegenerative diseases.
• Manipulating autophagy may lead to therapeutics for neurodegenerative diseases.

Autophagy is an evolutionarily conserved lysosomal degradation pathway that removes damaged organelles and protein aggregates from the cytoplasm. Being post-mitotic, neurons are particularly vulnerable to the accumulation of proteotoxins and are thus heavily dependent on autophagy to maintain homeostasis. In fact, CNS-specific and neuron-specific loss of autophagy is sufficient to cause neurodegeneration in mice. Further, mutations in genes that encode PINK1 and Parkin, proteins that selectively remove damaged mitochondria, cause Parkinson’s disease, linking defective autophagy with neurodegenerative disease in humans. This review provides an overview of the mechanisms of autophagy in the axon and the role of neuronal autophagy in axonal homeostasis and degeneration. The pathway for autophagosome biogenesis and maturation along the axon will be discussed as well as several key insights revealing the diverse functions of axonal autophagy. Evidence linking altered autophagy with axonal degeneration and neuronal death will be presented. Appropriate manipulation of autophagy may lead to promising therapeutics for neurodegenerative diseases.This article is part of a Special Issue entitled SI:Autophagy.