Intranasal Delivery of Caspase-9 Inhibitor Reduces Caspase-6-Dependent Axon/Neuron Loss and Improves Neurological Function after Stroke

Akpan, Nsikan; Serrano-Saiz, Esther; Zacharia, Brad E.; Otten, Marc L.; Ducruet, Andrew F.; Snipas, Scott J.; Li, Wen; Velloza, Jennifer; Cohen, Guy; Sosunov, Sergeyi A.; Frey, William H.; Salvesen, Guy S.; Connolly, E. Sander; Troy, Carol M.

doi:10.1523/jneurosci.0698-11.2011

Cited by 84 publications

(87 citation statements)

References 50 publications

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“…Oxidative stress, a trigger for apoptosis, induced by the addition of hydrogen peroxide in HEK 293/Tau cells, increases active caspase-6 and caspase-3 activity (72). An increase in caspase-6 activity has also been documented in global brain ischemia (73) Caspase-6 Helix-Strand Interconversion and acute ischemic stroke (74), where slight intracellular acidification has been observed to acidify slightly to pH 6.43 (75). Although the precise role of the two-state conformations of caspase-6 is still not known, pH changes in the context of neurodegeneration could conformationally enrich caspase-6 in either helical or strand conformations.…”

Section: Discussionmentioning

confidence: 99%

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

Dagbay¹,

Bolik-Coulon²,

Savinov

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellCaspases are cysteine aspartate proteases that are major players in key cellular processes, including apoptosis and inflammation. Specifically, caspase-6 has also been implicated in playing a unique and critical role in neurodegeneration; however, structural similarities between caspase-6 and other caspase active sites have hampered precise targeting of caspase-6. All caspases can exist in a canonical conformation, in which the substrate binds atop a ␤-strand platform in the 130's region. This caspase-6 region can also adopt a helical conformation that has not been seen in any other caspases. Understanding the dynamics and interconversion between the helical and strand conformations in caspase-6 is critical to fully assess its unique function and regulation. Here, hydrogen/deuterium exchange mass spectrometry indicated that caspase-6 is inherently and dramatically more conformationally dynamic than closely related caspase-7. In contrast to caspase-7, which rests constitutively in the strand conformation before and after substrate binding, the hydrogen/ deuterium exchange data in the L2 and 130's regions suggested that before substrate binding, caspase-6 exists in a dynamic equilibrium between the helix and strand conformations. Caspase-6 transitions exclusively to the canonical strand conformation only upon substrate binding. Glu-135, which showed noticeably different calculated pK a values in the helix and strand conformations, appears to play a key role in the interconversion between the helix and strand conformations. Because caspase-6 has roles in several neurodegenerative diseases, exploiting the unique structural features and conformational changes identified here may provide new avenues for regulating specific caspase-6 functions for therapeutic purposes.Caspases are cysteine proteases that recognize aspartatecontaining substrates and are major players in key cellular processes, including apoptosis and inflammation. Caspase active sites contain a Cys-His dyad required for cleavage of peptide bonds adjacent to aspartate residues in select protein substrates. There are two main classes of caspases, initiator and executioner caspases, classified based on their cellular function and domain organization. Initiator caspases (caspase-2, -8, and -9) function upstream in the apoptotic pathway and activate the downstream executioner caspases (caspase-3, -6, and -7) by proteolytic cleavage at an intersubunit linker between large and small subunits. Executioner caspases then cleave a select group of protein targets to promote apoptosis. Initiator caspases generally exist as monomers and are subsequently activated by dimerization mediated by interaction with a molecular platform (e.g.

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Section: Discussionmentioning

confidence: 99%

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

Dagbay¹,

Bolik-Coulon²,

Savinov

et al. 2017

Journal of Biological Chemistry

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“…While intriguing given the evidence of APP accumulation in injured axons, whether this system is applicable to ischemic axonal injury remains unclear. Recent work by Akpan et al [59] demonstrated that caspase-9 activation occurs early after transient middle cerebral artery occlusion (tMCAO) triggering activation of the caspase-6-dependent axonal degeneration pathway in the ischemic penumbra. In a novel translational approach, this group used intranasal caspase-9 inhibition to block axonal degeneration after stroke and improve functional recovery.…”

Section: The Back: Progressive Axonal Degeneration After Strokementioning

confidence: 99%

The back and forth of axonal injury and repair after stroke

Hinman¹

2014

Current Opinion in Neurology

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Purpose of review The axon plays a central role in both the injury and repair phases after stroke. This review highlights emerging principles in the study of axonal injury in stroke and the role of the axon in neural repair after stroke. Recent findings Ischemic stroke produces a rapid and significant loss of axons in the acute phase. This early loss of axons results from a primary ischemic injury that triggers a wave of calcium signaling, activating proteolytic mechanisms and downstream signaling cascades. A second progressive phase of axonal injury occurs during the subacute period and damages axons that survive the initial ischemic insult but go on to experience a delayed axonal degeneration driven in part by changes in axoglial contact and axonal energy metabolism. Recovery from stroke is dependent on axonal sprouting and reconnection that occurs during a third degenerative/regenerative phase. Despite this central role played by the axon, comparatively little is understood about the molecular pathways that contribute to early and subacute axonal degeneration after stroke. Recent advances in axonal neurobiology and signaling suggest new targets that hold promise as potential molecular therapeutics including axonal calcium signaling, axoglial energy metabolism and cell adhesion as well as retrograde axonal mitogen-activated protein kinase pathways. These novel pathways must be modeled appropriately as the type and severity of axonal injury vary by stroke subtype. Summary Stroke-induced injury to axons occurs in three distinct phases each with a unique molecular underpinning. A wealth of new data about the molecular organization and molecular signaling within axons is available but not yet robustly applied to the study of axonal injury after stroke. Identifying the spatiotemporal patterning of molecular pathways within the axon that contribute to injury and repair may offer new therapeutic strategies for the treatment of stroke.

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“…Nikolaev et al showed that the inhibition of DR6 protects axons and neurons by inhibiting caspase-6 and caspase-3 activation after trophic deprivation [14]. Some authors report that the inhibition of caspase-9 reduces caspase-6-dependent axon and neuron loss and improves neurological function after stroke [18]. Other authors have found that caspase-6 inhibition enhances both survival and regeneration of injured retinal ganglion cells [19].…”

Section: Axon Regeneration Is Inhibited In Nerve Injury Diseasesmentioning

confidence: 99%

A new therapy for the reduction of axon and neuron loss and promotion of axon and oligodendrocyte regeneration through inhibition of death receptor 6 pathway after ischemic cerebral stroke

2012

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Intranasal Delivery of Caspase-9 Inhibitor Reduces Caspase-6-Dependent Axon/Neuron Loss and Improves Neurological Function after Stroke

Cited by 84 publications

References 50 publications

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding

The back and forth of axonal injury and repair after stroke

A new therapy for the reduction of axon and neuron loss and promotion of axon and oligodendrocyte regeneration through inhibition of death receptor 6 pathway after ischemic cerebral stroke

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