Piezo1 Mediates Ultrasound-Stimulated Dopaminergic Neuron Protection via Synaptic Vesicle Recycling and Ferroptosis Inhibition
Tian Xu, Li Zhang, Xiaoxiao Lu, Wei Ji, Kaidong Chen
Neuroscience Bulletin 2025 · 10.1007/s12264-025-01420-5
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/cm 2 ) 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.
Abstract via europepmc.
Exposures
Exposure 1: SH-SY5Y PD cell model, continuous US at 610, 746 and 1000 kHz
Target: cultured neurons — “differentiated SH-SY5Y cells (MPP+ PD model)”
Device: other named manufacturer · Jiangsu Hanmei Science and Technology Co., Ltd · HM-1 therapeutic device ✓
| Waveform | continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 610, 746, 1,000swept | ✓✓✓ |
| Pulse duration (ms) | not applicable | |
| Pulse repetition frequency (Hz) | not applicable | |
| Duty cycle (%) | not applicable | ⚑ |
| Sonication duration (s) | 40 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not applicable | |
| In-situ pressure (kPa) | not applicable | |
| In-situ Isppa (W/cm²) | not applicable | |
| In-situ Ispta (W/cm²) | not applicable | |
| Ispta, domain unspecified (W/cm²) | 0.1, 0.3swept | ✓?⚑ |
Continuous US applied to cells in plates for 40 s per well at three frequencies and graded intensities; optimum 610 kHz and 0.20 W/cm2.
Exposure 2: MPTP mice, 610 kHz 0.2 W/cm2 daily for 7 days
Target: brain — “head, where US transducers were located (striatum analysed)”
Device: other named manufacturer · Jiangsu Hanmei Science and Technology Co., Ltd · HM-1 therapeutic device ✓
| Waveform | continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 610 | ✓✓✓ |
| Pulse duration (ms) | not applicable | |
| Pulse repetition frequency (Hz) | not applicable | |
| Duty cycle (%) | not applicable | |
| Sonication duration (s) | 900 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Ispta, domain unspecified (W/cm²) | 0.2 | ✓?⚑ |
Daily 15-min US stimulation at 610 kHz and 0.2 W/cm2 for 7 days under isoflurane anaesthesia; target position on head not stated.
Flags from extraction
exposures[0].unspecified_domain.ispta_w_cm2— Paper says only 'intensity' measured with a US power meter before sonication; whether spatial-peak temporal-average and in which medium is not stated. Results text gives 0.05 to 0.25 W/cm2 for the same sweep while Methods give 0.1 to 0.3 W/cm2.exposures[1].unspecified_domain.ispta_w_cm2— Intensity type and domain not stated; placed in unspecified_domain.n_subjects— Forty mice in four groups of about ten; only the PD+US and PD+US+GsMTx4 groups were sonicated. Cell experiments not counted.exposures[1].target.terms— Mouse sonication site not described beyond transducer on depilated head; striatal samples analysed. Target term 'brain' is a placeholder.exposures[0].timing.duty_cycle_pct— Continuous wave; duty cycle not stated so left null.