Calpain 1 Knockdown Improves Tissue Sparing and Functional Outcomes after Spinal Cord Injury in Rats

Yu, Chiang; Li, Yanzhang; Raza, Kashif; Yu, Xin; Ghoshal, Sakti Prasad; Geddes, James W.

doi:10.1089/neu.2012.2561

Cited by 23 publications

(18 citation statements)

References 35 publications

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“…The expression level of calpain markedly increases a few hours after SCI [39][40][41][42] , especially in motoneurons 43 . The activation of calpain 1, but not of calpain 2, contributes to initial reactive gliosis and tissue damage after SCI 40,44,45 , but calpain activity is confined to the injury site 46 . In regard to the calpain-mediated upregulation of I NaP , this observation is compatible with the small I NaP recorded in sacral motoneurons after acute SCI 24 .…”

Section: Discussionmentioning

confidence: 99%

Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

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Plantier

Boulenguez

et al. 2016

Nat Med

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Upregulation of the persistent sodium current (I(NaP)) in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate I(NaP) and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels after neonatal SCI was associated with an upregulation of I(NaP) in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of I(NaP). The pharmacological inhibition of calpain activity by MDL28170 reduced the cleavage of Nav channels, I(NaP) in motoneurons and spasticity in rats with SCI. Similarly, the blockade of I(NaP) by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of I(NaP) and spasticity.

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Section: Discussionmentioning

confidence: 99%

Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

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Plantier

Boulenguez

et al. 2016

Nat Med

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“…Since the discovery of the first calpain in 1964 (Guroff, 1964), it is now recognized that the human genome contains 15 genes encoding calpain-like proteases (Sorimachi et al, 2010). The ubiquitously expressed μ - and m-calpain are a focus of investigation in the diseased nervous system (Bevers et al, 2010; Geddes and Saatman, 2010; Yu et al, 2013). μ - and m-calpain are heterodimers that consist of 80 kDa catalytic subunits sharing 55-65% sequence homology (calpain 1 and calpain 2, respectively) and a common 28 kDa regulatory subunit, known as calpain 4 or common small subunit 1 (CSS1; Goll et al, 2003).…”

Section: The Calpain/calpastatin Systemmentioning

confidence: 99%

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

2013

Neurobiology of Disease

106

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Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed.

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“…Some studies have observed prosurvival roles for CAPN-1 activation but destructive roles for CAPN-2 activation in retinal ganglion cell degeneration [17,19]. However, in a recent rat contusive spinal cord injury model, CAPN-1 was activated and contributed to impaired locomotor function [16]. These differences might be explained by the preferential participation of CAPN isoforms to different cellular functions even in different substructures of the same cells [14,35].…”

Section: Discussionmentioning

confidence: 99%

“…Eleven types of calpain isoforms have been identified in humans so far, of which calpain-1 (µ-calpain, CAPN-1) and calpain-2 (m-calpain, CAPN-2) are the most widely ubiquitous isoforms in the central nervous system (CNS) [13]. Being distributed in the same subcellular localization (cytoplasm) and sharing a common small subunit (known as CAPN-4) upon activation, CAPN-1 and CAPN-2 seem to have similar biochemical properties [13,16]. CAPN-1 and CAPN-2 have previously been demonstrated to be overactivated in various models of neurodegenerative diseases and injury, although they require micromolar and millimolar calcium levels for activation, respectively [13,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…Being distributed in the same subcellular localization (cytoplasm) and sharing a common small subunit (known as CAPN-4) upon activation, CAPN-1 and CAPN-2 seem to have similar biochemical properties [13,16]. CAPN-1 and CAPN-2 have previously been demonstrated to be overactivated in various models of neurodegenerative diseases and injury, although they require micromolar and millimolar calcium levels for activation, respectively [13,[14][15][16]. However, in contrast to traditional views, some studies have recently suggested that CAPN-1 activation plays prosurvival roles whereas CAPN-2 plays neurodegenerative roles, based on their opposite functions in promoting neuronal plasticity following CNS injury [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Roles of the miR-137-3p/CAPN-2 gene pair in ischemia-reperfusion-induced neuronal apoptosis through modulation of p35 cleavage and subsequent caspase-8 overactivation

Zhang

et al. 2019

Preprint

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Background: Neuron survival after ischemia-reperfusion (IR) injury is the primary determinant of motor function prognosis. MicroRNA (miR)-based gene therapy has gained attention. Our previous work explored the mechanisms by which miR-137-3p modulates neuronal apoptosis in both in vivo and in vitro IR models.Methods: IR-induced motor dysfunction and spinal calpain (CAPN) subtype expression and subcellular distribution were detected within 12 h post IR. Dysregulated miRs, including miR-137-3p, were identified by miR microarray analysis and confirmed by PCR. Luciferase assay confirmed that CAPN-2 is a corresponding target of miR-137-3p, and their modulation of motor function was evaluated by intrathecal infection with synthetic miRs. CAPN-2 activity was measured by the intracellular Ca2+ concentration and mean fluorescence intensity in vitro. Neuronal apoptosis was detected by flow cytometry and lactate dehydrogenase (LDH) release. The activities of p35, p25, Cdk5 and caspase-8 were evaluated by ELISA and Western blotting after transfection with specific inhibitors and miRs.Results: The IR-induced motor dysfunction time course was closely associated with CAPN-2 protein upregulation, which was mainly distributed in neurons. The miR-137-3p/CAPN-2 gene pair was confirmed by luciferase assay. miR-137-3p mimic significantly improved IR-induced motor dysfunction and decreased CAPN-2 expression, even in combination with recombinant rat calpain-2 (rr-CALP2) injection, whereas miR-137-3p inhibitor reversed these effects. Similar changes were observed in the intracellular Ca2+ concentration and CAPN-2 expression and activity when cells were exposed to OGD/R and transfected with synthetic miRs in vitro. Moreover, double fluorescence revealed that CAPN-2, p35, p25 and caspase-8 were all identically distributed in neurons. The decrease in CAPN-2 expression and activity was accompanied by the opposite changes in p35 activity and protein expression in cells transfected with miR-137-3p mimic, roscovitine (a Cdk5 inhibitor) or Z-IETD-FMK (a caspase-8 inhibitor). Correspondingly, more surviving neurons were observed with the abovementioned treatments, indicated by a decrease in apoptotic cell percentage, LDH release and p25, Cdk5, caspase-8 and caspase-3 protein expression.Conclusions: The miR-137-3p/CAPN-2 gene pair functions to modulate neuronal apoptosis during IR injury, possibly through CAPN-2 inhibition leading to p35 cleavage and inhibition of subsequent p25/Cdk5 and caspase-8 overactivation.

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Calpain 1 Knockdown Improves Tissue Sparing and Functional Outcomes after Spinal Cord Injury in Rats

Cited by 23 publications

References 35 publications

Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

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

Roles of the miR-137-3p/CAPN-2 gene pair in ischemia-reperfusion-induced neuronal apoptosis through modulation of p35 cleavage and subsequent caspase-8 overactivation

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