Syndecan-3 as a Novel Biomarker in Alzheimer’s Disease

Hudák, Anett; Letoha, Annamária; Vízler, Csaba; Letoha, Tamás

doi:10.3390/ijms23063407

Cited by 17 publications

(7 citation statements)

References 86 publications

(121 reference statements)

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“…However, this has been proposed as a compensatory mechanism in response to autogenic syndecan-3 depletion or functional alteration, since syndecan-1 and syndecan-3 have redundant features [ 19 ]. Interestingly, syndecan-3 is implicated in the pathology of Alzheimer’s disease [ 25 ], but no relationship to ALS has been reported yet. It is important to remark that the reanalysis of the potential pathogenic gene variants from a previous ALS study confirmed the absence of pathogenic variants of Piezo2 and Piezo1 [ 15 ].…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…However, the therapeutic application of AAV9 and the development of novel, CNS-specific AAV serotypes are hindered by the limited knowledge of AAV9 receptors, especially those on the BBB. To explore the potential AAV9 receptors on the BBB, we examined AAV9’s entry into hCMEC/D3 cells, a human BBB model cell line with moderate SDC4 expression [ 62 , 63 ]. Efficient SDC4 knockdown significantly reduced AAV9-mediated gene delivery in AAV9-treated (4 × 10 4 vg/cell at 37 °C for 72 h) hCMEC/D3 cells.…”

Section: Resultsmentioning

confidence: 99%

Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9

Hudák¹,

Roach

Pusztai³

et al. 2023

IJMS

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Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9’s cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9’s cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9’s cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS.

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“…Both syndecans and glypicans have been shown to transport chemokines across peripheral vascular beds (39). The function of syndecans and glypicans as transcytotic transporters of the BBB is underexplored, however a few studies have reported expression of syndecans 2-4 in brain endothelial cells, whereas glypicans are expressed at lower levels or absent (40)(41)(42). Both human and mouse RNAseq datasets of brain microvessels did not detect syndecan-1 (40), which is thought to predominate in the peripheral vasculature, or glypican-2.…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate-dependent transport of CCL2 across an in vitro model of the human blood-brain barrier

Williams

Fujimoto

Weaver

et al. 2023

Preprint

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Background: Transport of immune-active substances across the blood-brain barrier (BBB) is an important mechanism of neuroimmune regulation. CCL2 is among the chemokines known to cross the intact BBB in the blood-to-brain direction and is supported to do so in mice through interactions with heparan sulfate (HS)-containing components of the endothelial glycocalyx. The goal of this study was to characterize blood-to-brain transport mechanisms of human CCL2 in a human induced pluripotent stem-cell (iPSC)- derived in vitro model of the BBB. Methods: Human brain endothelial-like cells (iBECs) were differentiated using established methods and then changed to heparin-free medium. All experiments were conducted 9 days after seeding differentiated iBECs on permeable culture inserts or tissue culture plates. Human recombinant CCL2 and bovine serum albumin (Alb) as a leakage tracer was labeled with 125I and 131I, respectively, and their flux across the monolayer was quantified by calculating the permeability-surface area coefficient. Transport of 125I-CCL2 and 131I-Alb was evaluated at baseline, in the presence of a CCR2 inhibitor and heparin, following treatment with heparinases, and following treatment with the heparan sulfate synthesis inhibitor GalNaz to evaluate HS-dependent mechanisms of transport. We further determined the mechanism of 125I-CCL2 transcytosis using inhibitors of clathrin, caveolae, and dynamin. Results: We found that iBECs have a functional blood-to-brain transport system for CCL2. Similar to our previous findings in mice, heparin inhibited CCL2 transport whereas the CCR2 inhibitor did not. We further showed that both heparinase treatment and treatment with GalNaz inhibited CCL2 transport across the BBB, supporting the requirement for HS in CCL2 transport. CCL2 transcytosis was clathrin-independent and caveolae and dynamin-dependent. Conclusions: Our findings support that human CCL2 is transported across the human BBB in vitro by a mechanism that was HS-dependent, caveolae and dynamin-dependent, and clathrin-independent. Our findings underscore the utility of iBECs for the study of mechanisms of heparan sulfate/glycocalyx interactions in the transport of substances across the BBB.

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Syndecan-3 as a Novel Biomarker in Alzheimer’s Disease

Cited by 17 publications

References 86 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

Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9

Heparan sulfate-dependent transport of CCL2 across an in vitro model of the human blood-brain barrier

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