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<p>Recent investigations underscore the pivotal role of reactive astrocytes in the pathogenesis of Parkinson’s disease (PD). As PD advances, reactive astrocytes lose their ability to degrade α-Synuclein (α-Syn) aggregates while concurrently increasing <i>r</i>-aminobutyric acid (GABA) secretion, which heightens inhibition of DA neurons and worsens the disease. This study explored optogenetic manipulation of reactive astrocytes as a therapeutic strategy. Halorhodopsin (NpHR), a chloride pump, was expressed in reactive astrocytes within the substantia nigra pars compacta (SNpc) of an A53T α-Syn overexpression PD rat model. Optogenetic stimulation of NpHR led to a 72.6% reduction in GABA level (<i>p</i> = 0.0486) and a 67.5% decrease in α-Syn aggregates (<i>p</i> &lt; 0.0001) within the SNpc. Furthermore, contralateral forelimb akinesia was significantly improved by 81.4 ± 7.2% (71.6–90.9%) post-illumination in the NpHR group compared with the pre-illumination state (<i>p</i> = 0.0002). These results suggest that the optogenetic modulation of reactive astrocytes can alleviate astrocytic aberrant tonic inhibition of DA neurons, resulting in the revitalization of DA neurons and enhancing the degradation of α-Syn aggregates. This mechanism may ultimately ameliorate parkinsonian motor symptoms, suggesting a promising novel therapeutic avenue for PD.</p>

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Optogenetic regulation of chloride ions in reactive astrocytes may mitigate Parkinson’s disease pathology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Eun Jung Lee,
  • Hyung Ho Yoon,
  • Sang Ryong Jeon

摘要

Recent investigations underscore the pivotal role of reactive astrocytes in the pathogenesis of Parkinson’s disease (PD). As PD advances, reactive astrocytes lose their ability to degrade α-Synuclein (α-Syn) aggregates while concurrently increasing r-aminobutyric acid (GABA) secretion, which heightens inhibition of DA neurons and worsens the disease. This study explored optogenetic manipulation of reactive astrocytes as a therapeutic strategy. Halorhodopsin (NpHR), a chloride pump, was expressed in reactive astrocytes within the substantia nigra pars compacta (SNpc) of an A53T α-Syn overexpression PD rat model. Optogenetic stimulation of NpHR led to a 72.6% reduction in GABA level (p = 0.0486) and a 67.5% decrease in α-Syn aggregates (p < 0.0001) within the SNpc. Furthermore, contralateral forelimb akinesia was significantly improved by 81.4 ± 7.2% (71.6–90.9%) post-illumination in the NpHR group compared with the pre-illumination state (p = 0.0002). These results suggest that the optogenetic modulation of reactive astrocytes can alleviate astrocytic aberrant tonic inhibition of DA neurons, resulting in the revitalization of DA neurons and enhancing the degradation of α-Syn aggregates. This mechanism may ultimately ameliorate parkinsonian motor symptoms, suggesting a promising novel therapeutic avenue for PD.