Details

Autor(en) / Beteiligte

• Soman, Smijin K.
• Tingle, David
• Dagda, Raul Y.
• Torres, Mariana
• Dagda, Marisela
• Dagda, Ruben K.

Titel

Cleaved PINK1 induces neuronal plasticity through PKA‐mediated BDNF functional regulation

Ist Teil von

• Journal of neuroscience research, 2021-09, Vol.99 (9), p.2134-2155

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Wiley Online Library Journals【キャンパス外アクセス可】

Beschreibungen/Notizen

• Mutations in PTEN‐induced kinase 1 (PINK1) lead 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 the 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 brain‐derived neurotrophic factor (BDNF). Consistent with this role, we observed a progressive increase in the level of endogenous cPINK1 but not fPINK1 during prenatal and postnatal development of mouse brains and during development in primary cortical neurons. In cultured primary neurons, the pharmacological activation of endogenous PINK1 leads to enhanced downstream PKA activity, subsequent activation of the PKA‐modulated transcription factor cAMP response element‐binding protein (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. In healthy mitochondria, cleaved PINK1 retro‐translocates to the cytosol, where it phosphorylates and activates protein kinase A (PKA). PKA activation results in the PKA‐mediated phosphorylation of cAMP response element‐binding protein (CREB), which subsequently relocates to the nucleus to promote the transcription of genes in CRE‐localized domains. Brain‐derived neurotrophic factor (BDNF) is one of the targets of CREB‐mediated transcription. BDNF gets transcribed, translated, post‐translationally cleaved, and released into the extracellular space, where it binds to the TRKβ receptor and triggers the synaptic delivery of PSD95.