Role of lipid composition on the structural and mechanical features of axonal membranes: a molecular simulation study

Saeedimasine, Marzieh; Montanino, Annaclaudia; Kleiven, Svein; Villa, Alessandra

doi:10.1038/s41598-019-44318-9

Cited by 85 publications

(75 citation statements)

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“…Interestingly, poration both in presence and absence of protein takes place in bilayer regions lacking ganglioside lipids (Figure 7). Ganglioside-type lipids are mainly found in the outer leaflet of the membrane and are known to make the lipid bilayer more resistant to deformation due to the interactions between sugar headgroups (30).…”

Section: Resultsmentioning

confidence: 99%

“…Previous experimental studies have in fact focused on areal deformations of red blood cells (RBCs) (27). Molecular simulations studies have investigated mechanoporation by deforming two-to-four component lipid bilayer biaxially (28)(29)(30). Given the slenderness of the axons, however, during stretchinjury one can expect the axolemma to deform mainly along the axial direction.…”

Section: Introductionmentioning

confidence: 99%

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Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

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Morphological choicesAs now reported in the main text of the manuscript, given the axon cross-section and the proposed MTs densities (Bray and Bunge 1981, Fadic et al. 1985, Malbouisson et al. 1985) 19 rows of MTs were included in the axon RV, each containing two randomly placed discontinuities. The same approach was used in Peter and Mofrad (2012), Lazarus et al. (2015), Soheilypour et al. (2015). Mechanical properties of the MTs have been very well identifies by previous studies. Material properties These filaments represent the stiffest part of the cytoskeleton and the Youngs' modulus (E=830 MPa) was derived by Zhang et al. (2014) with a numerical approach and was in extremely good agreement with experiments by de Pablo et al (2003)where MTs are locally probed. In the latter study, older bending experiments (which estimate a modulus E=1 to 1.2 GPa) were considered to overestimate the material properties of MTs because they usually probe length scales much longer than the one necessary to assess material properties. Being these filaments far stiffer then the remainder of our model, it can be said that a slightly stiffer modulus would not affect the localization of strains on the membrane. Tau proteins:Morphological choices Cross-connection between microtubules (MTs) and between neurofilaments (NFs) and MTs were quantified in a seminal study by Hirokawa (1982). There, MTs crosslinks were found to be less abundant than those between neurofilaments, which were reported having a 30-50 nm spacing. Inspecting the microscopy images in the same publication, a spacing of 120 nm was chosen for our model. Previous studies have also shown, through a sensitivity study, that tau protein density does not influence the energy associated with MTs stretching. Material propertiesCompared to the MTs, the material properties of these filaments are far less studied. The properties that we chose are based on previous studies by Ahmadzadeh et al (2014,2015). In these studies the viscoelastic characteristic of these cross-links was derived from previous experimental studies. While the spring stiffness is in the range of previously tested motor proteins (kinesin stiffness = uN/m ), we agree that its viscous component is the biggest assumption behind our model, which would however would affect mostly the microtubule Bray, D. and Bunge, M.B., 1981. Serial analysis of microtubules in cultured rat sensory axons. ., 2003. Deformation and collapse of microtubules on the nanometer scale. Physical review letters, 91(9), p.098101. Hirokawa, N., 1982. Cross-linker system between neurofilaments, microtubules and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. The Journal of cell biology, 94(1), pp.129-142. Ahmadzadeh, H., Smith, D.H. and Shenoy, V.B., 2014. Viscoelasticity of tau proteins leads to strain rate-dependent breaking of microtubules during axonal stretch injury: predictions from a mathematical model. Biophysical journal, 106(5), pp.1123-1133. Ahmadzadeh, H., Smith, D.H. and Shenoy, V.B., 2015. Mech...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

et al. 2020

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“…Ganglioside-type lipids are mainly found in the outer leaflet of the membrane and are known to make the lipid bilayer more resistant to deformation due to the interactions between sugar headgroups. 30…”

Section: Resultsmentioning

confidence: 99%

“…Secondly, an accurate representation of the membrane lipid content was deemed necessary to assess features such as membrane permeability and poration given that lipid content is known to have an influence on membrane’s mechanical properties. 28,30,31,33…”

Section: Discussionmentioning

confidence: 99%

“…27 Molecular simulations studies have investigated mechanoporation by deforming two-to-four component lipid bilayer biaxially. 28–30 Given the slenderness of the axons, however, during stretch-injury one can expect the axolemma to deform mainly along the axial direction. Not only loading mode specificity, but also material specificity might also play a key role in the understanding of axonal injury.…”

Section: Introductionmentioning

confidence: 99%

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Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Montanino

Saeedimasine

Villa

et al. 2019

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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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Ultrathin 2D Titanium Carbide MXene (Ti₃C₂T_x) Nanoflakes Activate WNT/HIF‐1α‐Mediated Metabolism Reprogramming for Periodontal Regeneration

Cui

Kong

Ding

et al. 2021

Adv Healthcare Materials

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Periodontal defect regeneration in severe periodontitis relies on the differentiation and proliferation of periodontal ligament cells (PDLCs).Recently, an emerging 2D nanomaterial, MXene (Ti 3 C 2 T x ), has gained more and more attention due to the extensive antibacterial and anticancer activity, while its potential biomedical application on tissue regeneration remains unclear. Through a combination of experimental and multiscale simulation schemes, Ti 3 C 2 T x has exhibited satisfactory biocompatibility and induced distinguish osteogenic differentiation of human PDLCs (hPDLCs), with upregulated osteogenesis-related genes. Ti 3 C 2 T x manages to activate the Wnt/𝜷-catenin signaling pathway by enhancing the Wnt-Frizzled complex binding, thus stabilizing HIF-1𝜶 and altering metabolic reprogramming into glycolysis. In vivo, hPDLCs pretreated by Ti 3 C 2 T x display excellent performance in new bone formation and osteoclast inhibition with enhanced RUNX2, HIF-1𝜶, and 𝜷-catenin in an experimental rat model of periodontal fenestration defects, indicating that this material has high efficiency of periodontal regeneration promotion. It is demonstrated in this work that Ti 3 C 2 T x has highly efficient therapeutic effects in osteogenic differentiation and periodontal defect repairment.

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Role of lipid composition on the structural and mechanical features of axonal membranes: a molecular simulation study

Cited by 85 publications

References 65 publications

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Ultrathin 2D Titanium Carbide MXene (Ti₃C₂T_x) Nanoflakes Activate WNT/HIF‐1α‐Mediated Metabolism Reprogramming for Periodontal Regeneration

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Role of lipid composition on the structural and mechanical features of axonal membranes: a molecular simulation study

Cited by 85 publications

References 65 publications

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Ultrathin 2D Titanium Carbide MXene (Ti3C2Tx) Nanoflakes Activate WNT/HIF‐1α‐Mediated Metabolism Reprogramming for Periodontal Regeneration

Contact Info

Product

Resources

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Ultrathin 2D Titanium Carbide MXene (Ti₃C₂T_x) Nanoflakes Activate WNT/HIF‐1α‐Mediated Metabolism Reprogramming for Periodontal Regeneration