Axons at the Heart of Neurodegenerative Diseases

Axons, the long extensions of neurons, play a central role in brain function. Their deterioration, known as axonopathy, is now recognized as an early and major mechanism in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. These unique structures, sometimes over a meter long, ensure the rapid transmission of nerve signals and the transport of essential molecules between the cell body and synapses. Their vulnerability stems from both their complex organization and their dependence on a stable cellular environment.

Axons are surrounded by a myelin sheath that accelerates the conduction of electrical signals. Their function also relies on a bidirectional transport system, where molecular motors move organelles, proteins, and vesicles along microtubules. When this transport is disrupted, toxic proteins accumulate, such as beta-amyloid in Alzheimer’s disease or alpha-synuclein in Parkinson’s disease. These aggregates block axonal traffic and trigger a cascade of dysfunctions.

Glial cells, such as astrocytes and microglia, actively contribute to axonal health. However, in pathological conditions, they become agents of degeneration. For example, astrocytes lose their ability to provide metabolic support, while excessively activated microglia release inflammatory molecules that damage axons. The loss of myelin, often observed in these diseases, exposes axons and worsens their vulnerability.

Recent advances show that early disruptions in endosomal traffic within axons, such as the hyperactivation of the Rab5 protein, promote the accumulation of toxic proteins and the degradation of organelles. These mechanisms are reinforced by genetic mutations that affect the regulation of transport or the degradation of cellular waste.

Targeting axons and their glial environment opens new therapeutic avenues. Strategies aim to restore axonal transport, modulate glial cell activity, or enhance energy production in axons. Molecules capable of stabilizing microtubules, normalizing Rab5 activity, or improving axonal metabolism are under investigation. These approaches could slow the progression of neurodegenerative diseases by protecting these essential structures even before symptoms appear.

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DOI: https://doi.org/10.1186/s40035-026-00543-7

Title: Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases

Journal: Translational Neurodegeneration

Publisher: Springer Science and Business Media LLC

Authors: Ruinan Shen; Kijung Sung; Jianqing Ding; Chengbiao Wu