Heat shock protein A12A encodes a novel prosurvival pathway during ischaemic stroke

Heat shock protein A12A (HSPA12A) is a newly discovered member of the Hsp70 family. The biological characteristics and functional roles of HSPA12A are poorly understood. This study investigated the effects of HSPA12A on ischaemic stroke in mice. Ischaemic stroke was induced by left middle cerebral artery occlusion for 1 h followed by blood reperfusion. We observed that HSPA12A was highly expressed in brain neurons, and neuronal HSPA12A expression was downregulated by ischaemic stroke and stroke-associated risk factors (aging, obesity and hyperglycaemia). To investigate the functional requirement of HSPA12A in protecting ischaemic brain injury, HSPA12A knockout mice (Hspa12a^-/-) were generated. Hspa12a^-/- mice exhibited an enlarged infarct volume and aggravated neurological deficits compared to their wild-type (WT) littermates after stroke. These aggravations in Hspa12a^-/- mice were accompanied by more apoptosis and severer hippocampal morphological abnormalities in ischaemic hemispheres. Long-term examination revealed impaired motor function recovery and neurogenesis in stroke-affected Hspa12a^-/- mice compared to stroke-affected WT controls. Significant reduced activation of GSK-3β/mTOR/p70S6K signalling was also observed in ischaemic hemispheres of Hspa12a^-/- mice compared to WT controls. Administration with lithium (non-selective GSK-3β inhibitor) activated GSK-3β/mTOR/p70S6K signalling in stroke-affected Hspa12a^-/- mice. Notably, lithium administration attenuated the HSPA12A deficiency-induced aggravation in infarct size, neurological deficits and neuronal death in Hspa12a^-/- mice after stroke. Altogether, the findings suggest that HSPA12A expression encodes a critical novel prosurvival pathway during ischaemic stroke. We identified HSPA12A as a novel neuroprotective target for stroke patients.