Intracellular calcium release through IP 3 R or RyR contributes to secondary axonal degeneration

Orem, Ben C.; Pelisch, Nicolas; Williams, Joshua; Nally, Jacqueline M.; Stirling, David P.

doi:10.1016/j.nbd.2017.07.011

Cited by 21 publications

(10 citation statements)

References 46 publications

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“…RyR2 in CA lesions may contribute to axonal dysfunction because intra-axonal Ca 2+ overload mediated by RyRs and IP3Rs activates the mitochondrial permeability transition pore and contributes to axonal dieback and degeneration following WM ischemic injury (Ouardouz et al, 2003 ; Stirling and Stys, 2010 ; Kesherwani and Agrawal, 2012 ) and SCI (Stirling et al, 2014 ; Liao et al, 2016 ). The RyRs inhibitor ryanodine significantly attenuates mitochondrial dysfunction (Villegas et al, 2014 ), axonal dieback, and secondary axonal degeneration in injured WM (Thorell et al, 2002 ; Stirling et al, 2014 ; Orem et al, 2017 ). In line, mice with RyR2 gain-of-function mutation exhibit more axonal damage than wild-type controls following SCI (Stirling et al, 2014 ), while RyR2 knockdown attenuates mitochondrial dysfunction and ER stress and improves functional recovery (Liao et al, 2016 ).…”

Section: K + Channelsmentioning

confidence: 99%

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Boscia

Elkjaer

Illés

et al. 2021

Front. Cell. Neurosci.

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Despite significant advances in our understanding of the pathophysiology of multiple sclerosis (MS), knowledge about contribution of individual ion channels to axonal impairment and remyelination failure in progressive MS remains incomplete. Ion channel families play a fundamental role in maintaining white matter (WM) integrity and in regulating WM activities in axons, interstitial neurons, glia, and vascular cells. Recently, transcriptomic studies have considerably increased insight into the gene expression changes that occur in diverse WM lesions and the gene expression fingerprint of specific WM cells associated with secondary progressive MS. Here, we review the ion channel genes encoding K+, Ca2+, Na+, and Cl− channels; ryanodine receptors; TRP channels; and others that are significantly and uniquely dysregulated in active, chronic active, inactive, remyelinating WM lesions, and normal-appearing WM of secondary progressive MS brain, based on recently published bulk and single-nuclei RNA-sequencing datasets. We discuss the current state of knowledge about the corresponding ion channels and their implication in the MS brain or in experimental models of MS. This comprehensive review suggests that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain, while the upregulation of a large number of voltage-gated K+ channel genes may be linked to a protective response to limit neuronal excitability. In addition, the altered chloride homeostasis, revealed by the significant downregulation of voltage-gated Cl− channels in MS lesions, may contribute to an altered inhibitory neurotransmission and increased excitability.

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Section: K + Channelsmentioning

confidence: 99%

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Boscia

Elkjaer

Illés

et al. 2021

Front. Cell. Neurosci.

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“…Xestospongin C (Xec) and ryanodine (Rya) are specific antagonists of IP3R and RyR, respectively. All of them have been demonstrated with critical role in regulation of Ca 2+ homeostasis and therapeutic potential in multiple disorders, like diabetes and neurodegenerative disease .…”

Section: Introductionmentioning

confidence: 99%

Impaired calcium homeostasis via advanced glycation end products promotes apoptosis through endoplasmic reticulum stress in human nucleus pulposus cells and exacerbates intervertebral disc degeneration in rats

et al. 2019

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Previous studies identified advanced glycation end products (AGEs) accumulation in the intervertebral disc (IVD) as an essential risk factor associated with IVD degeneration via accelerated cell apoptosis and impeded extracellular‐matrix metabolism; however, the underlying mechanisms have not been fully elucidated. Here, we investigated the effects and mechanisms of AGEs‐mediated apoptosis in vitro and in vivo. We evaluated the effects of AGEs on endoplasmic reticulum (ER) stress, apoptosis, and subcellular calcium (Ca2+) redistribution. Our data indicated time‐ and concentration‐dependent upregulation of ER‐stress responses in AGEs‐treated nucleus pulposus (NP) cells. Additionally, we observed marked suppression of AGEs‐mediated apoptosis following the inhibition of ER stress using 4‐phenylbutyric acid. Moreover, AGEs‐induced sustained cytosolic Ca2+ ([Ca2+]c) elevation and ER luminal Ca2+ ([Ca2+]er) depletion in a concentration‐ and time‐dependent manner in NP cells. Furthermore, we observed significant increases and decreases in levels of the ER‐resident Ca2+‐release channels inositol 1,4,5‐triphosphate receptor and ryanodine receptor and ER Ca2+‐reuptake pumps sarco/endoplasmic reticulum Ca2+‐ATPase, respectively. Pharmacologically blocking ER Ca2+ release using Ca2+ antagonists significantly ameliorated Ca2+ dyshomeostasis, ER stress, and subsequent apoptosis in NP cells and partially attenuated the progression of IVD degeneration in vivo. These results demonstrated that impaired Ca2+ homeostasis plays an essential role in AGEs‐mediated ER stress and subsequent apoptosis in NP cells, with blockage of ER Ca2+ release partially ameliorating subcellular Ca2+ redistribution, ER stress, and apoptosis. Our findings provide novel mechanistic insight into the role of AGEs in the pathogenesis of IVD degeneration and a potential therapeutic strategy.

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“…NAD + depletion after injury leads to the increase of relative concentrations of calcium-mobilizing agents including cADPR and ADPR over axonal NAD + , stimulating intra-axonal calcium rise by activation of ryanodine receptors on ER and calcium channels on plasma membrane, respectively 56 . In addition, blocking ER calcium channels has been shown to protect injury-induced axonal degeneration in DRG cultures and secondary degeneration of severed CNS axons 57,58 . However, whether blocking intracellular calcium stores would suppress spheroid formation on injured sympathetic axons must be investigated in the future.…”

Section: Discussionmentioning

confidence: 99%

Regulation of degenerative spheroids after injury

Gamage

Cushman

et al. 2020

Sci Rep

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Neuronal injury leads to rapid, programmed disintegration of axons distal to the site of lesion. Much like other forms of axon degeneration (e.g. developmental pruning, toxic insult from neurodegenerative disorder), Wallerian degeneration associated with injury is preceded by spheroid formation along axons. The mechanisms by which injury leads to formation of spheroids and whether these spheroids have a functional role in degeneration remain elusive. Here, using neonatal mouse primary sympathetic neurons, we investigate the roles of players previously implicated in the progression of Wallerian degeneration in injury-induced spheroid formation. We find that intra-axonal calcium flux is accompanied by actin-Rho dependent growth of calcium rich axonal spheroids that eventually rupture, releasing material to the extracellular space prior to catastrophic axon degeneration. Importantly, after injury, Sarm1−/− and DR6−/−, but not Wlds (excess NAD+) neurons, are capable of forming spheroids that eventually rupture, releasing their contents to the extracellular space to promote degeneration. Supplementation of exogenous NAD+ or expressing WLDs suppresses Rho-dependent spheroid formation and degeneration in response to injury. Moreover, injured or trophically deprived Sarm1−/− and DR6−/−, but not Wlds neurons, are resistant to degeneration induced by conditioned media collected from wild-type axons after spheroid rupture. Taken together, these findings place Rho-actin and NAD+ upstream of spheroid formation and may suggest that other mediators of degeneration, such as DR6 and SARM1, mediate post-spheroid rupture events that lead to catastrophic axon disassembly.

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Intracellular calcium release through IP 3 R or RyR contributes to secondary axonal degeneration

Cited by 21 publications

References 46 publications

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Impaired calcium homeostasis via advanced glycation end products promotes apoptosis through endoplasmic reticulum stress in human nucleus pulposus cells and exacerbates intervertebral disc degeneration in rats

Regulation of degenerative spheroids after injury

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