Axonal spheroids in neurodegeneration

• Published in: Molecular and cellular neuroscience 2021-12, Vol.117, p.103679-103679, Article 103679
• Main Authors: Yong, Yu, Hunter-Chang, Sarah, Stepanova, Ekaterina, Deppmann, Christopher
• Format: Article
• Language: English
• Subjects: Axonal spheroids; Axons; Cytoskeleton; Degeneration; Humans; Neurodegenerative disease; Neurodegenerative Diseases
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2021.103679

Axonal spheroids are bubble-like biological features that form on most degenerating axons, yet little is known about their influence on degenerative processes. Their formation and growth has been observed in response to various degenerative triggers such as injury, oxidative stress, inflammatory factors, and neurotoxic molecules. They often contain cytoskeletal elements and organelles, and, depending on the pathological insult, can colocalize with disease-related proteins such as amyloid precursor protein (APP), ubiquitin, and motor proteins. Initial formation of axonal spheroids depends on the disruption of axonal and membrane tension governed by cytoskeleton structure and calcium levels. Shortly after spheroid formation, the engulfment signal phosphatidylserine (PS) is exposed on the outer leaflet of spheroid plasma membrane, suggesting an important role for axonal spheroids in phagocytosis and debris clearance during degeneration. Spheroids can grow until they rupture, allowing pro-degenerative factors to exit the axon into extracellular space and accelerating neurodegeneration. Though much remains to be discovered in this area, axonal spheroid research promises to lend insight into the etiologies of neurodegenerative disease, and may be an important target for therapeutic intervention. This review summarizes over 100 years of work, describing what is known about axonal spheroid structure, regulation and function. •Axonal spheroids accumulate disease-associated proteins, organelles, and cytoskeletal elements .•Axonal cytoskeleton rearrangements and membrane rupture cause influx of ions like calcium, promoting spheroid formation and growth.•Spheroids can recruit phagocytes via phosphatidylserine, indicating a potential role for spheroids in cellular waste elimination.•Spheroid contents can activate pro-degeneration receptors and known degeneration pathways.