Piezo1 Mediates Ultrasound-Stimulated Dopaminergic Neuron Protection via Synaptic Vesicle Recycling and Ferroptosis Inhibition
Tian Xu1 · Li Zhang2,3 · Xiaoxiao Lu4 · Wei Ji5 · Kaidong Chen2,31 School of Environmental Science and Engineering, Wuxi University, Wuxi 214105, China
2 Department of Neurology, The Afliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China
3 Department of Functional Neurology, The Afliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China
4 Tai’an Center for Disease Control and Prevention, Tai’an 271000, China
5 Department of Neurosurgery, The Afliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) and dysregulated synaptic vesicle (SV) recycling. Emerging evidence suggests that ferroptosis is the target of PD therapy. However, the identification of effective anti-ferroptosis treatments remains elusive. This study explores the therapeutic potential of low-intensity ultrasound (US) in modulating SV recycling and anti-ferroptosis in cellular and animal models of PD. We demonstrate that optimized US stimulation (610 kHz, 0.2 W/cm2) activates Piezo1 channel-mediated fast endophilin-mediated endocytosis, which promotes SV recycling and synaptic function, presenting with increased frequency and amplitude of both spontaneous excitatory synaptic currents and miniature excitatory postsynaptic currents. Repaired SV recycling in turn reduces the accumulation of α-syn expression and ferroptotic cell death. These findings support the potential of noninvasive ultrasonic neuromodulation as a therapeutic strategy for PD and lead to meaningful health outcomes for the aging population.
Keywords
Low intensity ultrasound; Neuromodulation; Parkinson’s Disease; Piezo1; Ferroptosis; Synaptic vesicle recycling
