Calpain Activation in Experimental Glaucoma

Huang, Wei; Fileta, John B.; Rawe, Ian; Qu, Juan; Grosskreutz, Cynthia L.

doi:10.1167/iovs.09-4364

Cited by 58 publications

(38 citation statements)

References 35 publications

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“…Spectrin organizes the subaxolemmal actin scaffold that, among other functions, confers strength to axons (Xu et al, 2013), enabling it to resist mechanical stresses (Elson, 1988; Zhou et al, 1999; Jung et al, 2005; Xu et al, 2013). While we were unable to detect SBDP in any DBA/2J or control retina (in contrast to previous findings by Huang et al (2010) who found elevated SBDP in an experimentally-induced ocular hypertension model), we did observe high levels of calpain-mediated spectrin breakdown product in the ON and SC of our pre-pathological, young DBA/2J mice. This result was somewhat unexpected, as elevated IOP, transport deficits, and axon loss are not typically present in DBA/2J at 3–5 months.…”

Section: Discussioncontrasting

confidence: 99%

“…Cleaved α-II spectrin has been found in varicosities and end bulb swellings (Uryu et al, 2007) and is shown to be upregulated in the retina of rodent glaucoma models with elevated IOP (Huang et al, 2010). Spectrin organizes the subaxolemmal actin scaffold that, among other functions, confers strength to axons (Xu et al, 2013), enabling it to resist mechanical stresses (Elson, 1988; Zhou et al, 1999; Jung et al, 2005; Xu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma

Wilson¹,

Smith²,

Inman³

et al. 2016

Front. Neurosci.

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Axonal transport deficits precede structural loss in glaucoma and other neurodegenerations. Impairments in structural support, including modified cytoskeletal proteins, and microtubule-destabilizing elements, could be initiating factors in glaucoma pathogenesis. We investigated the time course of changes in protein levels and post-translational modifications in the DBA/2J mouse model of glaucoma. Using anterograde tract tracing of the retinal projection, we assessed major cytoskeletal and transported elements as a function of transport integrity in different stages of pathological progression. Using capillary-based electrophoresis, single- and multiplex immunosorbent assays, and immunofluorescence, we quantified hyperphosphorylated neurofilament-heavy chain, phosphorylated tau (ptau), calpain-mediated spectrin breakdown product (145/150 kDa), β–tubulin, and amyloid-β42 proteins based on age and transport outcome to the superior colliculus (SC; the main retinal target in mice). Phosphorylated neurofilament-heavy chain (pNF-H) was elevated within the optic nerve (ON) and SC of 8–10 month-old DBA/2J mice, but was not evident in the retina until 12–15 months, suggesting that cytoskeletal modifications first appear in the distal retinal projection. As expected, higher pNF-H levels in the SC and retina were correlated with axonal transport deficits. Elevations in hyperphosphorylated tau (ptau) occurred in ON and SC between 3 and 8 month of age while retinal ptau accumulations occurred at 12–15 months in DBA/2J mice. In vitro co-immunoprecipitation experiments suggested increased affinity of ptau for the retrograde motor complex protein dynactin. We observed a transport-related decrease of β-tubulin in ON of 10–12 month-old DBA/2J mice, suggesting destabilized microtubule array. Elevations in calpain-mediated spectrin breakdown product were seen in ON and SC at the earliest age examined, well before axonal transport loss is evident. Finally, transport-independent elevations of amyloid-β42, unlike pNF-H or ptau, occurred first in the retina of DBA/2J mice, and then progressed to SC. These data demonstrate distal-to-proximal progression of cytoskeletal modifications in the progression of glaucoma, with many of these changes occurring prior to complete loss of functional transport and axon degeneration. The earliest changes, such as elevated spectrin breakdown and amyloid-β levels, may make retinal ganglion cells susceptible to future stressors. As such, targeting modification of the axonal cytoskeleton in glaucoma may provide unique opportunities to slow disease progression.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma

Wilson¹,

Smith²,

Inman³

et al. 2016

Front. Neurosci.

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“…30,34,35 Calpain and the cleaved form of calcineurin are activated in glaucoma or through high intraocular pressure, 34,35 both leading to RGC cell death. 30 However, calpain-induced calcineurin cleavage in excitotoxic neurodegeneration can be blocked by calpain inhibitors such as FK506 (Tacrolimus) or CSA.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine A Protects RGC-5 Cells From Excitotoxic Cell Death

Schultheiß

Schnichels

Młyńczak

et al. 2014

Journal of Glaucoma

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“…The activity of calpains can be examined by many methods, including immunodetection of calpain cleavage products (Stys and Jiang, 2002) or zymography (Raser et al, 1995). Calpain activity is linked to RGC axonal degeneration in oxidative stress Russo et al, 2011;Stys and Jiang, 2002;Tamada et al, 2005;Yokoyama et al, 2014) and elevated IOP (Huang et al, 2010;Oka et al, 2006).…”

Section: Cyclin Dependent Kinase 5 Calcineurin and Calpainmentioning

confidence: 99%

Assessment of retinal ganglion cell damage in glaucomatous optic neuropathy: Axon transport, injury and soma loss

Nuschke

Farrell

Levesque

et al. 2015

Experimental Eye Research

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Calpain Activation in Experimental Glaucoma

Abstract: These data support the hypothesis that calpain is activated under conditions of elevated intraocular pressure and provide further details of the pathologic events leading to RGC loss in glaucoma.

Cited by 58 publications

References 35 publications

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma

Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma

Cyclosporine A Protects RGC-5 Cells From Excitotoxic Cell Death

Assessment of retinal ganglion cell damage in glaucomatous optic neuropathy: Axon transport, injury and soma loss

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