Subthalamic nucleus deep brain stimulation protects neurons by activating autophagy via PP2A inactivation in a rat model of Parkinson's disease

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Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for alleviating disability in patients with moderate to severe Parkinson's disease (PD). Preclinical studies have shown that stimulation of the rat STN can protect against nigral dopaminergic neuron loss. However, the underlying mechanism is unclear. To investigate the molecular basis of the neuroprotective effects of STN stimulation, a rat model of PD was established by unilaterally injecting 6-hydroxydopamine (6-OHDA) into the striatum. PD rats were subjected to DBS of the STN (STN-DBS) and the effects on motor symptoms and number of nigral tyrosine hydroxylase-positive (TH+) neurons was examined. We found that STN-DBS improved movement disorder and mitigated the loss of TH+ neurons induced by 6-OHDA. Furthermore, STN-DBS blocked protein phosphatase (PP)2A activation induced by 6-OHDA and led to the phosphorylation of B cell lymphoma (Bcl)-2, thereby increasing its activity. This induced its disassociation from Beclin1, a positive regulator of autophagy, leading to autophagy and inhibition of apoptosis. These findings demonstrate for the first time that STN-DBS could exert neuroprotective effects against 6-OHDA-induced cell injury in PD by inducing autophagy via PP2A inactivation and dissociation of the Bcl-2/Beclin1 complex, thereby providing a molecular basis of STN-DBS neuroprotection for PD.

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