Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon

Ma, Marek

doi:10.1016/j.nbd.2013.08.010

Cited by 103 publications

(86 citation statements)

References 211 publications

(391 reference statements)

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“…Calpain deficiencies as well as its over-activation are linked to a variety of diseases and pathological consequences (21). Because of their multifaceted nature, they control various irreversible signaling events and biological functions in the cell such as endothelial cell adhesion, differentiation, migration, proliferation, cell cycle control, cytoskeletal remodeling, embryonic development, and vesicular trafficking (12)(13)(14)(22)(23)(24). Our studies support a relationship between calpains and microvascular permeability at the level of the BBB.…”

Section: Discussionsupporting

confidence: 58%

“…Calpain-1 is activated under low calcium concentrations (3-50 M), whereas calpain-2 is activated only under high concentrations (400 -800 M) of calcium in the cell (23,24). Calpain-1 knockdown data from our studies demonstrate the contribution of calpain-1, but we do not disregard the contribution of calpain-2 in mediating BBB dysfunction and hyperpermeability, an area open for further investigation.…”

Section: Discussionmentioning

confidence: 58%

“…Calpain inhibitor III is a well studied cell-permeable pharmacological inhibitor of calpains (12), which was chosen for our in vitro and in vivo studies. Calpain inhibitor III crosses the BBB efficiently and binds specifically to calpains-1 and -2, unlike other inhibitors of calpains such as trypsin, plasmin, caspase-1, and cathepsin D (24). Cytoskeletal and neuroprotective properties of calpain inhibitor III were examined using the CCI model of TBI in male CF-1 mice, 24 h post-TBI (26).…”

Section: Discussionmentioning

confidence: 99%

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Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Alluri

Grimsley²,

Shaji

et al. 2016

Journal of Biological Chemistry

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Edited by Paul FraserBlood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability followed by brain edema are hallmark features of several brain pathologies, including traumatic brain injuries (TBI). Recent studies indicate that pro-inflammatory cytokine interleukin-1␤ (IL-1␤) that is upregulated following traumatic injuries also promotes BBB dysfunction and hyperpermeability, but the underlying mechanisms are not clearly known. The objective of this study was to determine the role of calpains in mediating BBB dysfunction and hyperpermeability and to test the effect of calpain inhibition on the BBB following traumatic insults to the brain. In these studies, rat brain microvascular endothelial cell monolayers exposed to calpain inhibitors (calpain inhibitor III and calpastatin) or transfected with calpain-1 siRNA demonstrated attenuation of IL-1␤-induced monolayer hyperpermeability. Calpain inhibition led to protection against IL-1␤-induced loss of zonula occludens-1 (ZO-1) at the tight junctions and alterations in F-actin cytoskeletal assembly. IL-1␤ treatment had no effect on ZO-1 gene (tjp1) or protein expression. Calpain inhibition via calpain inhibitor III and calpastatin decreased IL-1␤-induced calpain activity significantly (p < 0.05). IL-1␤ had no detectable effect on intracellular calcium mobilization or endothelial cell viability. Furthermore, calpain inhibition preserved BBB integrity/permeability in a mouse controlled cortical impact model of TBI when studied using Evans blue assay and intravital microscopy. These studies demonstrate that calpain-1 acts as a mediator of IL-1␤-induced loss of BBB integrity and permeability by altering tight junction integrity, promoting the displacement of ZO-1, and disorganization of cytoskeletal assembly. IL-1␤-mediated alterations in permeability are neither due to the changes in ZO-1 expression nor cell viability. Calpain inhibition has beneficial effects against TBI-induced BBB hyperpermeability.The blood-brain barrier (BBB) 2 plays an important role in maintaining the homeostasis of the brain. Blood-brain barrier breakdown and the associated hyperpermeability are hallmark features of several brain pathologies and injuries. The BBB is mainly composed of the cerebral endothelial cells and the tight junctions (TJs) between them (1). TJs between the neighboring endothelial cells include transmembrane TJs, i.e. occludin, claudins, junctional adhesion molecules, etc., and membranebound TJs, i.e. zonula occludens (1). Zonula occludens play an important role in regulating BBB permeability by binding to both transmembrane tight junctions and actin cytoskeleton intracellularly (2). Various mediators of inflammation are shown to modulate BBB breakdown and permeability in a variety of pathologies (3). Blood-brain barrier breakdown and the associated hyperpermeability is the leading cause of brain edema and elevated intracranial pressure followed by decreased perfusion pressure leading to poor clinical outcomes in traumatic brain injury (TBI) (4).I...

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Alluri

Grimsley²,

Shaji

et al. 2016

Journal of Biological Chemistry

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“…To determine whether axons that are at risk of fragmentation can still be rescued by therapeutic interventions initiated after injury, we pharmacologically inhibited the activity of calpain, a calcium- dependent protease implicated in axonal fragmentation [14][15][16] Fig. 5g,h).…”

Section: Resultsmentioning

confidence: 99%

A recoverable state of axon injury persists for hours after spinal cord contusion in vivo

et al. 2014

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Therapeutic strategies for spinal cord injury (SCI) commonly focus on regenerating disconnected axons. An alternative approach would be to maintain continuity of damaged axons, especially after contusion. The viability of such neuropreservative strategies depends on the degree to which initially injured axons can recover. Here we use morphological and molecular in vivo imaging after contusion SCI in mice to show that injured axons persist in a metastable state for hours. Intra-axonal calcium dynamics influence fate, but the outcome is not invariably destructive in that many axons with calcium elevations recover homeostasis without intervention. Calcium enters axons primarily through mechanopores. Spontaneous pore resealing allows calcium levels to normalize and axons to survive long term. Axon loss can be halted by blocking calcium influx or calpain, even with delayed initiation. Our data identify an inherent self-preservation process in contused axons and a window of opportunity for rescuing connectivity after nontransecting SCI.

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“…There are still many unanswered questions about the initiation factors, mechanism(s), and timing of axon injury in numerous diseases 77, 78, 79, 80, 81, 82, 83, 84. Axonopathy is ultimately driven by a confluence of factors and occurs via several intermediate and potentially reversible stages that eventually lead to irrevocable axonal degeneration 85.…”

Section: Discussionmentioning

confidence: 99%

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Clarkson

Patel

LaFrance‐Corey

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInjury‐associated axon‐intrinsic signals are thought to underlie pathogenesis and progression in many neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). Retrograde interferon gamma (IFN γ) signals are known to induce expression of major histocompatibility class I (MHC I) genes in murine axons, thereby increasing the susceptibility of these axons to attack by antigen‐specific CD8+ T cells. We sought to determine whether the same is true in human neurons.MethodsA novel microisolation chamber design was used to physically isolate and manipulate axons from human skin fibroblast‐derived induced pluripotent stem cell (iPSC)‐derived neuron‐enriched neural aggregates. Fluorescent retrobeads were used to assess the fraction of neurons with projections to the distal chamber. Axons were treated with IFN γ for 72 h and expression of MHC class I and antigen presentation genes were evaluated by RT‐PCR and immunofluorescence.ResultsHuman iPSC‐derived neural stem cells maintained as 3D aggregate cultures in the cell body chamber of polymer microisolation chambers extended dense axonal projections into the fluidically isolated distal chamber. Treatment of these axons with IFN γ resulted in upregulation of MHC class I and antigen processing genes in the neuron cell bodies. IFN γ‐induced MHC class I molecules were also anterogradely transported into the distal axon.InterpretationThese results provide conclusive evidence that human axons are competent to express MHC class I molecules, suggesting that inflammatory factors enriched in demyelinated lesions may render axons vulnerable to attack by autoreactive CD8+ T cells in patients with MS. Future work will be aimed at identifying pathogenic anti‐axonal T cells in these patients.

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Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon

Cited by 103 publications

References 211 publications

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

A recoverable state of axon injury persists for hours after spinal cord contusion in vivo

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

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