cPKC γ‐mediated down‐regulation of UCHL 1 alleviates ischaemic neuronal injuries by decreasing autophagy via ERK ‐ mTOR pathway

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 ( UCHL 1) 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 cPKC γ gene knockout remarkably aggravated ischaemic injuries and simultaneously increased the levels of cleaved (Cl)‐caspase‐3 and LC 3‐I proteolysis product LC 3‐ II , and the ratio of TUNEL ‐positive cells to total neurons. Moreover, cPKC γ gene knockout could increase UCHL 1 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 sh RNA of UCHL 1 significantly reduced the ratio of LC 3‐ II /total LC 3, which contributed to neuronal survival after ischaemic stroke, but did not alter the level of Cl‐caspase‐3. In addition, UCHL 1 sh RNA reversed the effect of cPKC γ on the phosphorylation levels of mTOR and ERK rather than that of AMPK and GSK ‐3β. In conclusion, our results suggest that cPKC γ activation alleviates ischaemic injuries of mice and cortical neurons through inhibiting UCHL 1 expression, which may negatively regulate autophagy through ERK ‐ mTOR pathway.