PINK1 has an alter ego: switching from controlling mitochondrial quality to stimulating neuronal plasticity through BDNF


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.

PINK1 has an alter ego: switching from controlling mitochondrial quality to stimulating neuronal plasticity through BDNF - Medicine Innovates

About the author

Ruben K. Dagda, Ph.D. received his doctoral training at the University of Iowa in 2006 and his postdoctoral training in neuropathology at the University of Pittsburgh School of Medicine in 2012. As an associate professor of Pharmacology at the University of Nevada, Reno School of Medicine, he is currently investigating the molecular mechanisms that lead to mitochondrial dysfunction and oxidative stress in cell culture, tissue and animal models of Parkinson’s and Alzheimer’s disease.

He has authored in 59 research manuscripts, review articles and book chapters in the areas of toxicology, toxinology, mitochondrial function, and neurobiology. At the University of Nevada, Reno School of Medicine, he is committed to the training and education of undergraduate, graduate students and postdocs in his lab and also manages an education research program to assist faculty from the Mountain West region attain career development skills. His main research goals are to elucidate the prosurvival signaling pathways that regulate mitochondrial function, transport and turn-over in neurons and how aging and neurodegenerative diseases negatively impact these processes. In addition, his research group is examining how mitochondrial PKA and PINK1 interact at the mitochondria and at the dendrites to regulate mitochondrial function, dendritic morphology and survival. The end goal is to develop novel small molecular drugs that can reverse neurodegeneration and elevate mitochondrial function in age-related neurodegenerative diseases. His research is currently funded by the National Institutes of Health and National Science Foundation.


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.

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