A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration

Efraim, Yael; Chen, Feeling Yu Ting; Cheong, Ka Neng; Gaylord, Eliza A.; McNamara, Nancy; Knox, Sarah M.

doi:10.1016/j.celrep.2022.111307

Cited by 8 publications

(8 citation statements)

References 77 publications

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“…Consequently, adequate syndecan supply and unimpaired extracellular surface representation seem to be needed in neuron activation and regeneration. In support, synthetic proteoglycans have been capable of reversing neuron regeneration disruption [ 90 ], most likely due to the redundant features of proteoglycans and syndecans. However, the chronic Piezo2 channelopathy in combination with functional syndecan depletion and underlying genetic mutations could make Piezo2 channelopathy irreversible, and this could be an important pathomechanistic link in ALS.…”

Section: The Metabolic Switchmentioning

confidence: 99%

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

Sonkodi

2024

Cells

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Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators.

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Section: The Metabolic Switchmentioning

confidence: 99%

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

Sonkodi

2024

Cells

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“…The aforementioned halted and incomplete functional regeneration is associated with a depletory picture in DE and RA not only in terms of the innate and adaptive immune system but in other terms as well. Correspondingly, a recent study demonstrated that a replenishing synthetic tear protein was capable of promoting corneal nerve regeneration even in the presence of associated chronic inflammation via restoring the depleted functional nerve supply [40]. That study was a breakthrough not only because it could provide the first regenerative treatment for DE in the future but because it also highlighted the critical importance of broken and dysfunctional nerve regeneration in the DE disease mechanism.…”

Section: Discussionmentioning

confidence: 93%

“…That study was a breakthrough not only because it could provide the first regenerative treatment for DE in the future but because it also highlighted the critical importance of broken and dysfunctional nerve regeneration in the DE disease mechanism. This is not to mention that the study of Efraim et al [40] most likely dissected two important pathomechanistic pathways with a potentially effective treatment with Lacripep. The principal pathway seemed to be nerve damage, and chronic ocular inflammation was only secondary.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis

Sonkodi

Csorba

Marsovszky

et al. 2023

IJMS

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The purpose of our study was to analyze abnormal neural regeneration activity in the cornea through means of confocal microscopy in rheumatoid arthritis patients with concomitant dry eye disease. We examined 40 rheumatoid arthritis patients with variable severity and 44 volunteer age- and gender-matched healthy control subjects. We found that all examined parameters were significantly lower (p < 0.05) in rheumatoid arthritis patients as opposed to the control samples: namely, the number of fibers, the total length of the nerves, the number of branch points on the main fibers and the total nerve-fiber area. We examined further variables, such as age, sex and the duration of rheumatoid arthritis. Interestingly, we could not find a correlation between the above variables and abnormal neural structural changes in the cornea. We interpreted these findings via implementing our hypotheses. Correspondingly, one neuroimmunological link between dry eye and rheumatoid arthritis could be through the chronic Piezo2 channelopathy-induced K2P-TASK1 signaling axis. This could accelerate neuroimmune-induced sensitization on the spinal level in this autoimmune disease, with Langerhans-cell activation in the cornea and theorized downregulated Piezo1 channels in these cells. Even more importantly, suggested principal primary-damage-associated corneal keratocyte activation could be accompanied by upregulation of Piezo1. Both activation processes on the periphery would skew the plasticity of the Th17/Treg ratio, resulting in Th17/Treg imbalance in dry eye, secondary to rheumatoid arthritis. Hence, chronic somatosensory-terminal Piezo2 channelopathy-induced impaired Piezo2–Piezo1 crosstalk could result in a mixed picture of disrupted functional regeneration but upregulated morphological regeneration activity of these somatosensory axons in the cornea, providing the demonstrated abnormal neural corneal morphology.

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“…Other lacritin proteoforms overlap with N-104. These include epithelial 30,74,75 and neuronal 31 regenerative, autophagic 29 and secretory 28,76–78 agonists. Some also act as surfactants 79 .…”

Section: Discussionmentioning

confidence: 99%

“…We previously discovered 'lacritin', a pleiotropic tear, salivary, plasma and CSF protein, out of an unbiased biochemical screen to address the biological basis of the most common ocular surface disease 28 . Lacritin transiently stimulates autophagy in the presence of inflammatory stress to restore oxidative phosphorylation 29 and promote both epithelial 30 and neuronal regeneration 31 .…”

Section: Lacritin 'N-104' Does Not Promote Bacterial Cell Lysismentioning

confidence: 99%

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

Sharifian Gh.,

Norouzi,

Sorci

et al. 2024

Preprint

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Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters.

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A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration

Cited by 8 publications

References 77 publications

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

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