Abstract
Autophagy is a promising target for promoting neural regeneration, which is essential for sensorimotor recovery following traumatic brain injury (TBI). Whether neuronal heat shock protein B2 (HSPB2), a small molecular heat shock protein, reduces injury and promotes recovery following TBI remains unclear. In this study, we demonstrated that HSPB2 was significantly increased in the neurons of a TBI mouse model, patients, and primary neuron cultures subjected to oxygen/glucose deprivation and reperfusion treatment. Upon creating a tamoxifen-induced neuron-specific HSPB2 overexpression transgenic mouse model, we found that elevated HSPB2 levels promoted long-term sensorimotor recovery and alleviated tissue loss after TBI. We also demonstrated that HSPB2 enhanced white matter structural and functional integrity, promoted central nervous system (CNS) plasticity, and accelerated long-term neural remodeling. Moreover, we found that autophagy occurred around injured brain tissues in patients, and the pro-regenerative effects of HSPB2 relied on its autophagy-promoting function. Mechanistically, HSPB2 may regulate autophagy possibly by forming the HSPB2/BCL2-associated athanogene 3/sequestosome-1 complex to facilitate the clearance of erroneously accumulated proteins in the axons. Treatment with the autophagy inhibitor chloroquine during the acute stage or delayed induction of HSPB2 remarkably impeded HSPB2's long-term reparative function, indicating the importance of acute-stage autophagy in long-term neuro-regeneration. Our findings highlight the beneficial role of HSPB2 in neuro-regeneration and functional recovery following acute CNS injury, thereby emphasizing the therapeutic potential of autophagy regulation for enhancing neuro-regeneration.