cPKCγ‐mediated down‐regulation ofUCHL1 alleviates ischaemic neuronal injuries by decreasing autophagyviaERK‐mTORpathway

Abstract

Stroke is one of the leading causes of death in the world, but its underlying mechanisms remain unclear. Both conventional protein kinase C (cPKC)γ and ubiquitin C‐terminal hydrolase L1 (UCHL1) are neuron‐specific proteins. In the models of 1‐hr middle cerebral artery occlusion (MCAO)/24‐hr reperfusion in mice and 1‐hr oxygen–glucose deprivation (OGD)/24‐hr reoxygenation in cortical neurons, we found that cPKCγ gene knockout remarkably aggravated ischaemic injuries and simultaneously increased the levels of cleaved (Cl)‐caspase‐3 and LC3‐I proteolysis product LC3‐II, and the ratio of TUNEL‐positive cells to total neurons. Moreover, cPKCγ gene knockout could increase UCHL1 protein expression via elevating its mRNA level regulated by the nuclear factor κB inhibitor alpha (IκB‐α)/nuclear factor κB (NF‐κB) pathway in cortical neurons. Both inhibitor and shRNA of UCHL1 significantly reduced the ratio of LC3‐II/total LC3, which contributed to neuronal survival after ischaemic stroke, but did not alter the level of Cl‐caspase‐3. In addition, UCHL1 shRNA reversed the effect of cPKCγ on the phosphorylation levels of mTOR and ERK rather than that of AMPK and GSK‐3β. In conclusion, our results suggest that cPKCγ activation alleviates ischaemic injuries of mice and cortical neurons through inhibiting UCHL1 expression, which may negatively regulate autophagy through ERK‐mTOR pathway.

IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

“…Whether autophagy is beneficial or detrimental depends upon the extent of autophagy induction and the duration of autophagy activation (36). Administration of 3-MA or Baf A1 largely protected them from cell death in primary cultured cortical neurons and significantly reduced MCAO/R-induced brain infarct volume, brain edema and motor deficits, suggesting autophagy contributes to cell death both in vitro and in vivo (16,17,37). In line with this, our results showed that autophagy was induced in OGD/R-treated neurons.…”

“…The activation of autophagy was witnessed in neurons after oxygen-glucose deprivation (OGD)/reoxygenation (R) and MCAO/R treatments (15)(16)(17). However, the role of autophagy and IL-17A in ischemic stroke are still ambiguous.…”

Protein Kinase C Isozymes and Autophagy during Neurodegenerative Disease Progression

“…Conventional PKCγ reduces neuron-specific autophagy via phosphorylation of mTOR on serine 2448 and serine 2481 [92]. It has been reported that cPKCγ provokes the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1) and is involved in the ERK-mTOR mediated autophagy during ischemic neural injury [93].…”

“…mTOR controls cell survival under growth-promoting factors and it has the ability to phosphorylate cPKC and Akt in order to establish protein stability [151]. The inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1) by cPKCγ restricts autophagy through the activation of ERK-mTOR pathway and reduces ischemic neural injury [93].…”

Serum ubiquitin C‐terminal hydrolase L1 predicts cognitive impairment in patients with acute organophosphorus pesticide poisoning

“…24 Circulating UCH-L1 has been identified as a biomarker specific to neuronal injury 16,25 as it is released into the circulation when the integrity of the blood-brain barrier (BBB) is disrupted. 26,27 In a piglet model, serum UCH-L1 predicted neuronal apoptosis induced by deep hypothermic circulatory arrest. 28 In observational studies, cerebrospinal fluid (CSF) and serum levels of UCH-L1 had utility as diagnostic and prognostic biomarkers of traumatic brain injury.…”