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Lysosomal Ca2+ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating autophagic/lysosomal dysfunction in neurons

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机构: [1]Kunming Univ Sci & Technol, Sch Basic Med Sci, Kunming 650500, Yunnan, Peoples R China [2]Kunming Univ Sci & Technol, Anning Peoples Hosp 1, Kunming 650500, Yunnan, Peoples R China
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关键词: Ischemic stroke Lysosomal Ca2+ Autophagic/lysosomal dysfunction TFEB TRPML1 Neuroprotection

摘要:
Neuronal death was frequently driven by autophagic/lysosomal dysfunction after ischemic stroke, whereas how to restore the impaired autophagic flux remained elusive. Autophagic/lysosomal signaling could be augmented after transcription factor EB (TFEB) nuclear translocation, which was facilitated by its dephosphorylation. A key TFEB dephosphorylase was calcineurin (CaN), whose activity was drastically regulated by cytosolic calcium ion concentration ([Ca2+]) controlled by lysosomal Ca2+ channel-like protein of TRPML1. Our research shows that ML-SA1, an agonist of the TRPML1 channel, significantly enhanced the lysosomal Ca2+ release and the CaN expression in penumbric neurons, subsequently promoted TFEB nuclear translocation, and greatly reversed autophagy/lysosome dysfunction. Moreover, ML-SA1 treatment significantly reduced neuronal loss, infarct size, and neurological deficits. By contrast, ML-SI3, an inhibitor of TRPML1, inhibited the lysosomal Ca2+ release conversely, aggravated the impairment of autophagic flux and consequentially exacerbated brain stroke lesion. These studies suggest that TRPML1 elevation alleviates ischemic brain injury by restoring autophagic/lysosomal dysfunction via Lysosomal Ca2+ release-facilitated TFEB nuclear translocation in neurons.

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大类 | 2 区 综合性期刊
小类 | 2 区 综合性期刊
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Q1 MULTIDISCIPLINARY SCIENCES
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Q1 MULTIDISCIPLINARY SCIENCES

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第一作者机构: [1]Kunming Univ Sci & Technol, Sch Basic Med Sci, Kunming 650500, Yunnan, Peoples R China
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通讯机构: [1]Kunming Univ Sci & Technol, Sch Basic Med Sci, Kunming 650500, Yunnan, Peoples R China [2]Kunming Univ Sci & Technol, Anning Peoples Hosp 1, Kunming 650500, Yunnan, Peoples R China
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