Modeling of the axon membrane skeleton structure and implications for its mechanical properties

Zhang, Yihao; Abiraman, Krithika; Li, He; Pierce, David M.; Tzingounis, Anastasios V.; Lykotrafitis, George

doi:10.1371/journal.pcbi.1005407

Cited by 78 publications

(89 citation statements)

References 56 publications

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“…We show that axonal actin rings are made of a small number of long, intertwined filaments rather than by a large number of short, bundled filaments as previously hypothesized Unsain et al, 2018b;Xu et al, 2013;Zhang et al, 2017). This short filament model was inferred from the presence of adducin at actin rings, at least along the distal axon Xu et al, 2013), because adducin was described as a capping protein that can bind to the barbed end of filaments (Kuhlman et al, 1996).…”

Section: Discussionsupporting

confidence: 68%

“…Finally, the arrangement of actin rings as a braid of long filaments is relevant to the observed stability of the MPS: closely apposed, intertwined filaments are likely to be resistant to severing factors such as ADF/cofilin (Michelot et al, 2007), and further stabilized by their embedding in the spectrin mesh. Rings made of long intertwined filaments are likely to be stiffer than bundled short filaments, hence could form the rigid part of a flexible and resistant scaffold when linked by elastic spectrins (Zhang et al, 2017), explaining the role of the MPS in the mechanical resistance of axons (Krieg et al, 2017). Beyond shedding light on the molecular underlaying of the MPS function, the ultrastructural insights obtained here could help understand its potential dysfunctions in neurodegenerative diseases, where the axonal integrity is often affected first (Encalada and Goldstein, 2014;Sleigh et al, 2019).…”

Section: Discussionmentioning

confidence: 90%

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Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings

Vassilopoulos

Gibaud

Jimenez

et al. 2019

Preprint

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Recent super-resolution microscopy studies have unveiled a periodic scaffold of actin rings regularly spaced by spectrins under the plasma membrane of axons. However, ultrastructural details are unknown, limiting a molecular and mechanistic understanding of these enigmatic structures. Here, we combine platinum-replica electron and optical super-resolution microscopy to investigate the cortical cytoskeleton of axons at the ultrastructural level. Immunogold labeling and correlative super-resolution/ electron microscopy allow us to unambiguously resolve actin rings as braids made of two long, intertwined actin filaments connected by a dense mesh of aligned spectrins. This molecular arrangement contrasts with the currently assumed model of actin rings made of short, capped actin filaments. Along the proximal axon, we resolved the presence of phospho-myosin light chain and the scaffold connection with microtubules via ankyrin G. We propose that braided rings explain the observed stability of the actin-spectrin scaffold and ultimately participate in preserving the axon integrity.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 90%

Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings

Vassilopoulos

Gibaud

Jimenez

et al. 2019

Preprint

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“…61 These elements were assigned a shear modulus G = 0.0016 MPa and a viscosity η =10 5 Pas. 62,63 Mechanical properties of all the model components can be found in Table 1. In a recent study, fluid friction was observed at the membrane-cortex interface with friction forces being proportional to the relative speed of the two layers.…”

Section: Methodsmentioning

confidence: 99%

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Montanino

Saeedimasine

Villa

et al. 2019

Preprint

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13Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With 14 almost 50% of traumatic brain injuries being related to axonal damage, understanding the 15 nature of cellular level impairment is crucial. Experimental observations have so far led to the 16 formulation of conflicting theories regarding the cellular primary injury mechanism. 17 Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly 18 as injury trigger. However, mechanoporation thresholds of generic membranes seem not to 19 overlap with the axonal injury deformation range and microtubules appear too stiff and too 20 weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the 21 mechanism of primary axonal injury, bridging finite element and molecular dynamics 22 simulations. Despite the necessary level of approximation, our models can accurately 23 describe the mechanical behavior of the unmyelinated axon and its membrane. More 24 importantly, they give access to quantities that would be inaccessible with an experimental 25 approach. We show that in a typical injury scenario, the axonal cortex sustains deformations 26 large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal 27 deformation of 10-12% agree well with the thresholds proposed in the literature for axonal 28 injury and, above all, allow us to provide quantitative evidences that do not exclude pore 29 formation in the membrane as a result of trauma. Our findings bring to an increased 30 knowledge of axonal injury mechanism that will have positive implications for the prevention 31 and treatment of brain injuries. 33 34Traumatic brain injury (TBI) is defined as "an alteration in brain function, or other evidence 2 of brain pathology, caused by an external force". 1 In 2013 approximately 2.8 million TBI-3 related emergency department visits, hospitalization, and deaths occurred in the United 4 States. 2 In a recent study reporting the epidemiology of TBI in Europe, Peeters and coworkers 5 analyzed data from 28 studies on 16 European countries and reported an average mortality 6 rate of ≈ 11 per 100,000 population over an incidence rate of 262 per 100,000 population per 7year. 3 Diffuse axonal injury (DAI), a multifocal damage to white matter axons, is the most 8 common consequence of TBIs of all severities including mild TBIs or concussions. 4 Invisible 9 to conventional brain imaging, DAI can only be histologically diagnosed and its hallmark is 10 the presence of axonal swellings or retraction balls observable under microscopic 11 examination. 5 12 13Considerable research effort has been put into the understanding of the primary effects of 14 trauma onto the neurons. To define an axonal injury trigger, nervous tissues and neuronal 15 cultures have been subjected to dynamic loads leading to several hypotheses regarding the 16 cell injury mechanism. Mechanoporation (i.e. the generation of membrane pores due to 17 mechanical deformation) of the axolemma has been his...

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“…autophagosomes 8 or mitochondria 9 , has been observed by super-resolution microscopy and 2D-electron microscopy (EM) in both normal and degenerating axons 10, 11 . Considering the spatial limitation exerted by the rigid axon membrane 12 , the trafficking of large cargoes is likely to be affected. In fact, a simulation study based on axon structure and intra-axonal microfluidic dynamics predicted that cargo trafficking was impeded by the friction from the axonal walls in small-calibre axons 13 .…”

Section: Introductionmentioning

confidence: 99%

Radial contractility of Actomyosin-II rings facilitates cargo trafficking and maintains axonal structural stability following cargo-induced transient axonal expansion

Wang

Martin

et al. 2018

Preprint

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17Most mammalian neurons have a narrow axon, which constrains the passage of large 18 cargoes such as autophagosome as they can be larger than the axon diameter. Variations 19 in tension must therefore occur radially to facilitate changes in axonal diameter and 20 ensure efficient axoplasmic trafficking. Here, we reveal that the transit of diverse large 21 membrane-bound cargoes causes an acute, albeit transient, radial expansion of the 22 axonal diameter, which is immediately restored by constricting forces. We demonstrate 23 that non-muscle myosin II (NM-II) forms ~200 nm periodic structures, which associate 24 with axonal F-actin rings. Inhibition of NM-II activity with blebbistatin significantly 25 increases axon diameter without affecting the periodicity of either the F-actin rings or 26 NM-II. This sustained radial expansion significantly affects the trafficking speed, 27 directionality, and reduces the overall efficiency of long-range retrograde axonal 28 cargoes, eventually leading to focal axon swelling and cargo accumulation, which are 29 hallmarks of axonal degeneration. 30 31 between 0.64 m and 0.74 m 3 . In contrast, the size of axonal cargoes is highly variable, 42 encompassing autophagosomes (0.5-1.5 m) 5 , mitochondria (0.75-3 m) 6 and 43 endosomes (50 nm-1 m) 7 . Thus, the range of cargo sizes is comparable to, or 44 surprisingly even larger than some of the CNS axons themselves. This advocates for 45 the existence of radial contractility in the axons, which would allow the transient 46 expansion of axon calibre and facilitate the passage of large cargoes. Indeed, the 47 expansion of axonal diameter surrounding large cargoes, i.e. autophagosomes 8 or 48 mitochondria 9 , has been observed by super-resolution microscopy and 2D-electron 49 microscopy (EM) in both normal and degenerating axons 10, 11 . Considering the spatial 50 limitation exerted by the rigid axon membrane 12 , the trafficking of large cargoes is 51 likely to be affected. In fact, a simulation study based on axon structure and intra-axonal 52 microfluidic dynamics predicted that cargo trafficking was impeded by the friction from 53 the axonal walls in small-calibre axons 13 . In line with this prediction, a correlation 54 between axon diameter and axon trafficking was recently reported in Drosophila 14, 15 55 and rodent neurons 16, 17 . However, direct evidence showing whether and how axonal 56 radial contractility affects cargo trafficking is still lacking. 57 58We hypothesized that the underlying structural basis for axonal radial contractility is 59 the subcortical actomyosin network, which is organized into specialized structures 60 called membrane-associated periodic cytoskeletal structures (MPS), as revealed with 61 super-resolution microscopy along the shafts of mature axons 18 . F-actin, together with 62 adducin and spectrin, forms a subcortical lattice with a ~190 nm periodic interval 63 covering the majority of the axon length 18, 19 . The disrupting of axonal F-actin leads to 64 loss of MPS 20, 21 , whereas the dep...

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Modeling of the axon membrane skeleton structure and implications for its mechanical properties

Cited by 78 publications

References 56 publications

Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings

Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Radial contractility of Actomyosin-II rings facilitates cargo trafficking and maintains axonal structural stability following cargo-induced transient axonal expansion

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