Rapid and Reversible Development of Axonal Varicosities: A New Form of Neural Plasticity

Abstract

Axonal varicosities are enlarged, heterogeneous structures along axonal shafts, profoundly affecting axonal conduction and synaptic transmission. They represent a key pathological feature believed to develop via slow accumulation of axonal damage that occurs during irreversible degeneration, for example in mild traumatic brain injury (mTBI), Alzheimer's and Parkinson's diseases, and multiple sclerosis. Here this review first discusses recent in vitro results showing that axonal varicosities can be rapidly and reversibly induced by mechanical stress in cultured primary neurons from the central nervous system (CNS). This notion is further supported by in vivo studies revealing the induction of axonal varicosities across various brain regions in different mTBI mouse models, as a prominent feature of axonal pathology. Limited progress in understanding intrinsic and extrinsic regulatory mechanisms of axonal varicosity induction and development is further highlighted. Rapid and reversible formation of axonal varicosities likely plays a key role in CNS neuron mechanosensation and is a new form of neural plasticity. Future investigation in this emerging research field may reveal how to reverse axonal injury, contributing to the development of new strategies for treating brain injuries and related neurodegenerative diseases.

SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy

“…Such S1 proteininduced endolysosome dysfunction could also disrupt the transport of synaptic vesicle precursors, lysosomes and autophagic components within both the axon and dendrites. Our results show that S1 protein enlarged lysosomes within these varicosities; a finding similar to that observed in Alzheimer's disease (Gowrishankar et al, 2015;Gu, 2021). However, further mechanistic investigations are warranted to understand the exact nature of these structures and how they form.…”

Opposing white matter microstructure abnormalities in 22q11.2 deletion and duplication carriers

“…We speculate that the neurological consequences of more densely packed WM might include reduced efficiency of electric signal transport or less effective extracellular matrix; however, preclinical studies investigating this possibility in 22q-del models have not yet been done. Indeed, previous research in (mild) traumatic brain injury and neurodegenerative disorders has suggested that axonal swellings or beading translate into disturbed axonal conduction and synaptic transmission [ 105 ]. However, we acknowledge that our interpretation is speculative, and future studies are needed to explore the underlying neurobiological basis of WM abnormalities in 22q11.2 CNV carriers.…”

A common theme for axonopathies? The dependency cycle of local axon homeostasis

“…To really understand the origin and progression of decay, we would need pathological timelines of events-but such systematic descriptions are rare (e.g., Spencer & Schaumburg, 1977a, 1977b probably as manifestations of a major pathway of CNS axonal death' (Coleman, 2005). Usually, these swellings are characterised by the accumulation of organelles and disorganisation or even disappearance of the cytoskeleton (Figure 2b, top; e.g., Berard-Badier, Gambarelli, Pinsard, Hassoun, & Toga, 1971;Bridge et al, 2009;Fassier et al, 2013;Fiala, Feinberg, Peters, & Barbas, 2007;Havlicek et al, 2014;Jellinger & Jirasek, 1971;Probst et al, 2000;Seitelberger, 1971;Tarrade et al, 2006;Yang et al, 1999); they are known to interfere with action potential propagation (Gu, 2021). (Figure 2a, top).…”