Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China; Neurosurgical Institute, Nanjing University, Nanjing, China.
Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Neurosurgical Institute, Nanjing University, Nanjing, China.
Exp Neurol. 2024 Oct;380:114904. doi: 10.1016/j.expneurol.2024.114904. Epub 2024 Jul 31.
Intact autophagy-lysosomal pathway (ALP) in neuronal survival is crucial. However, it remains unclear whether ALP is intact after subarachnoid hemorrhage (SAH). Ten-eleven translocation (TET) 3 primarily regulates genes related to autophagy in neurons in neurodegenerative diseases. This study aims to investigate the role of TET3 in the ALP following SAH. The results indicate that the ALP is impaired after SAH, with suppressed autophagic flux and an increase in autophagosomes. This is accompanied by a decrease in TET3 expression. Activation of TET3 by α-KG can improve ALP function and neural function to some extent. Silencing TET3 in neurons significantly inhibited the ALP function and increased apoptosis. Inhibition of miR-93-5p, which is elevated after SAH, promotes TET3 expression. This suggests that the downregulation of TET3 after SAH is, at least in part, due to elevated miR-93-5p. This study clarifies the key role of TET3 in the functional impairment of the ALP after SAH. The preliminary exploration revealed that miR-93-5p could lead to the downregulation of TET3, which could be a new target for neuroprotective therapy after SAH.
完整的自噬溶酶体途径（ALP）对于神经元存活至关重要。然而，蛛网膜下腔出血（SAH）后 ALP 是否完整仍不清楚。Ten-eleven translocation（TET）3 主要在神经退行性疾病中调节神经元中与自噬相关的基因。本研究旨在探讨 TET3 在 SAH 后 ALP 中的作用。结果表明，SAH 后 ALP 受损，自噬流受到抑制，自噬体增加。这伴随着 TET3 表达的减少。α-KG 激活 TET3 可以在一定程度上改善 ALP 功能和神经功能。神经元中 TET3 的沉默显著抑制了 ALP 功能并增加了细胞凋亡。SAH 后上调的 miR-93-5p 促进了 TET3 的表达。这表明，SAH 后 TET3 的下调至少部分是由于 miR-93-5p 的上调。本研究阐明了 TET3 在 SAH 后 ALP 功能障碍中的关键作用。初步探索表明，miR-93-5p 可能导致 TET3 的下调，这可能是 SAH 后神经保护治疗的一个新靶点。
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