Cleaved PINK1 induces neuronal plasticity through PKA-mediated BDNF functional regulation.
Cleaved PINK1 induces neuronal plasticity through PKA-mediated BDNF functional regulation.
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DOI：
10.1002/jnr.24854
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发表时间：
2021-09
影响因子：
4.2
通讯作者：
Dagda RK
中科院分区：
文献类型：
--
作者：
Soman SK;Tingle D;Dagda RY;Torres M;Dagda M;Dagda RK
Mutations in PTEN-induced Kinase 1 (PINK1) leads to early-onset autosomal recessive Parkinson’s disease in humans. In healthy neurons, full-length PINK1 (fPINK1) is post-translationally cleaved into different lower molecular weight forms, and cleaved PINK1 (cPINK1) gets shuttled to the cytosolic compartments to support extra-mitochondrial functions. While numerous studies have exemplified the role of mitochondrially-localized PINK1 in modulating mitophagy in oxidatively-stressed neurons, little is known regarding the physiological role of cPINK1 in healthy neurons. We have previously shown that cPINK1, but not fPINK1, modulates neurite outgrowth and the maintenance of dendritic arbors by activating downstream Protein Kinase A (PKA) signaling in healthy neurons. However, the molecular mechanisms by which cPINK1 promotes neurite outgrowth remain to be elucidated. In this report, we show that cPINK1 supports neuronal development by modulating the expression and extracellular release of BDNF. Consistent with this role, we observed a progressive increase in the level of endogenous cPINK1 but not fPINK1 during pre-natal and post-natal development of mouse brains and during development in primary cortical neurons. In cultured primary neurons, pharmacological activation of endogenous PINK1 leads to enhanced downstream PKA activity, subsequent activation of the PKA-modulated transcription factor CREB, increased intracellular production and extracellular release of BDNF, and enhanced activation of the BDNF receptor TRKβ. Mechanistically, cPINK1-mediated increased dendrite complexity requires the binding of extracellular BDNF to TRKβ. In summary, our data support a physiological role of cPINK1 in stimulating neuronal development by activating the PKA-CREB-BDNF signaling axis in a feedforward loop.
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影响因子：
5.4
作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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