The Axon and its Autophagy-Driven Homeostatic Control: Implications for the Onset of Human Neurodegenerative Diseases

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Submission deadlines

  1. Manuscript Summary Submission Deadline 22 April 2025 | Manuscript Submission Deadline 22 July 2025

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Background

The axon is the main neuronal process providing structure and intercellular communication in the nervous system. In mammals, it can extend up to a meter long and it must often survive far away from its cell body during the entire lifetime of the organism. This requires an outstanding homeostatic control in terms of energy, macromolecule synthesis and recycling, long-term maintenance of signaling networks like the ones elicited by calcium and reactive oxygen species. Neuron-specific knockout of genes essential for autophagosome formation showed that autophagy impairment is sufficient to induce axonal degeneration and neuron death in mice models: this suggests autophagy, as an evolutionarily conserved lysosomal degradation pathway for organelles and cytoplasmic material, is essential for the long-term maintenance of the axon. How autophagy regulates organelle homeostasis across the entire length of the axon poses a remarkable challenge from a cell biology point of view. Moreover, several mutations in genes encoding autophagy receptors and autophagy-related proteins have been linked to human, clinically untreatable neurodegenerative diseases: more knowledge about axonal autophagy is needed to better understand the pathogenicity of such mutations and to develop novel therapies against these devastating human conditions.

Recent research has focused on the role of autophagy in the context of neurogenesis and axon maintenance. For example, mutations of the autophagy receptor FAM134B have been linked with human sensory and autonomic neuropathy, a devastating condition characterized by loss of sensory neurons and impaired nociception, which in turn lead to often severe, self-inflicted mutilations. In this research field, the main challenge to cope with is the development of solid, reproducible, cost-affordable in vitro cellular models with neuronal specification. Induced pluripotent stem cells represented a groundbreaking innovation in neuron biology, but cell culture and differentiation conditions require highly specific skills and are monetarily demanding. Primary neuron culture is an equally daunting task due to the post-mitotic nature of such cells. This Research Topic aims to improve our understanding of axonal homeostasis and the implications for human neurodegenerative disease.

The scope of this Research Topic is to collect novel findings on the molecular mechanisms related to axonal autophagy that ultimately have implications on human health. We invite original research articles, as well as reviews and commentaries presenting novel views on recent developments in the field. We focus this issue on the following topics:

• Neuron-specific autophagy pathways affecting axon homeostasis: is the autophagy machinery used in the same way in neurons equipped with long axons (e.g. motoneurons) and short axons (e.g. Purkinje cells)?

• Intra-axonal cross talk between organelles, and between organelles and cytoskeleton

• Role of autophagy in determining neuronal differentiation

• Novel tools to study axonal structure and functionality, in vivo and in vitro

• Novel findings in genetics or molecular mechanisms involved in axonal degeneration and neuronal death

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  • Mini Review
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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

  • Brief Research Report
  • Data Report
  • Editorial
  • General Commentary
  • Hypothesis and Theory
  • Methods
  • Mini Review
  • Opinion
  • Original Research
  • Perspective
  • Review
  • Technology and Code

Keywords: autophagy, axon structure, axon functionality, neurodegenerative disease

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