Parkinson’s disease is the second most common neurodegenerative disease characterized by dopaminergic neuron degeneration in the substantia nigra, accompanied with locomotor defects. In most cases, Parkinson’s disease occurs sporadically as a result of many different environmental risk factors; mutations in a number of genes can also cause familial forms of Parkinson’s disease. Identification of the genes associated with parkinsonism has had a major impact on PD research, facilitating the dissection of the molecular mechanisms implicated in the pathogenesis of Parkinson’s disease. Autosomal recessive mutations in PTEN-induced kinase 1 (PINK1) have been blamed for causing the early onset of Parkinson’s disease in humans. Full-length PINK1 (fPINK1) in healthy mitochondria is cleaved into lower molecular weight forms. Cleaved PINK1 (cPINK1) subsequently gets shuttled to the cytosolic compartments to aid extra-mitochondrial functions.
Although several studies highlight the role of mitochondrial PINK1 in regulating the selective degradation of mitochondria by autophagy (mitophagy) in oxidatively stressed neurons, the physiological role of cPINK1 in healthy neurons is still unknown. Although PINK1 function is primarily mitophagy, new-found evidence suggests cPINK1 is critically involved in retrograde mitochondrial signaling to promote neuronal development. Moreover, cPINK1 has been identified as regulating the neurite outgrowth and maintains dendritic arbors by activating downstream protein kinase A signaling in healthy neurons. However, there is still a need to dissect on the molecular mechanisms by which cPINK1 enhances neurite outgrowths.
Brain-derived neurotrophic factor (BDNF) is a growth factor that regulates important neuronal functions, which include neuronal circuits development, neuronal survival modulation, and formation and maturation of dendritic spines. In both animal and human Parkinson’s disease models, reduced levels of BDNF have been reported in the nigrostriatal pathway. Therefore, attempts to increase BDNF to inhibit neurodegeneration are a therapeutic target.
In light of this, The University of Nevada researchers Smijin Soman, David Tingle, Raul Dagda, Mariana Torres, Marisela Dagda, and led by Professor Ruben Dagda sought to investigate the molecular mechanisms by which PINK1 revitalizes dendritic outgrowth. Through elegant molecular, experimental, and animal studies they reported that cPINK1 revitalized neuronal development by regulating BDNF signaling through downstream protein kinase A activation in healthy neurons. Their research work is published in the Journal of Neuroscience Research.
The authors findings showed a progressive increase in endogenous cleaved PINK1 levels than full-length PINK1 during prenatal and postnatal mice brain development and development in primary cortical neurons. The authors observed that pharmacological activation of endogenous PINK1 in cultured primary neurons leads to improved downstream protein kinase A activity.
Subsequently, when PINK1 activated the protein kinase A modulated transcription factors cAMP response element-binding protein (CREB), they reported an increase in intracellular and extracellular release of BDNF and an improved activation of its receptor TRKβ. cPINK1-mediated dendrite complexity required extracellular BDNF binding to TRKβ.
In all, the study findings reinforce the role of cPINK1 in activating neuronal development by initiating protein kinase A-CREB-BDNF signaling axis in a feedforward loop. The role of PINK1 in revitalizing BDNF signaling presents a new therapeutic intervention pathway in PD patients with cognitive impairment.
Smijin K. Soman, David Tingle, Raul Y. Dagda, Mariana Torres, Marisela Dagda, and Ruben K. Dagda. Cleaved PINK1 induces neuronal plasticity through PKA-mediated BDNF functional regulation. Journal of Neuroscience Research issue 99 (2021), pages 2134–2155.