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Silencing of PINK1 Inhibits Insulin-Like Growth Factor-1-Mediated Receptor Activation and Neuronal Survival

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Abstract

The etiology of Parkinson’s disease remains unknown. Mutations in PINK1 have provided an understanding of the molecular mechanisms of this pathology. PINK1 and Parkin are important in the dismissal of dysfunctional mitochondria. However, the role of PINK1 in the control of neuronal survival pathways is not clear. To determine the role of PINK1 in the control of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediated by insulin-like grow factor type 1 (IGF-1), we use a model of mesencephalic neurons (CAD cells), which were transfected with lentiviral PINK1 shRNA or control shRNA constructs. Silencing of PINK1 was determined by RT-PCR and immunoblotting; cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays; proteins of the PI3K/Akt signaling pathway were tested by immunoblotting and IGF-1 receptor, and mitochondria were examined using fluorescence microscopy. PINK1 shRNA-transfected cells showed a reduction in cell survival compared to control shRNA cells. Exposure to IGF-1 induced a rapid and high increase in the phosphorylation level of IGF-1 receptor in control shRNA-transfected cells; however, silencing of PINK1 decreases phosphorylation level of IGF-1 receptor and downstream target proteins such as Akt, GSK3-beta, IRS-1, and hexokinase. Our results further suggest that PINK1 may be regulating the PI3K/Akt neuronal survival pathway through tyrosine kinase receptors such as IGF-1 receptor.

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Abbreviations

OSIA:

Oxidative-stress-induced apoptosis

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Acknowledgments

PINK1 constructs were a kind gift from Dr. Mark Cookson (NIH, USA). CAD cells were a kind gift from Dr. Dona M. Chikaraishi, Department of Neurobiology, Duke University Medical Center, Durham NC, USA. This work was supported by a grant from COLCIENCIAS (110145221189).

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Authors and Affiliations

  1. Neuroscience and Cell Death Group, Faculty of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá, Colombia

    María J. Contreras-Zárate, Andrea Niño, Liliana Rojas, Humberto Arboleda & Gonzalo Arboleda

  2. Departamento de Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia

    Gonzalo Arboleda

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  1. María J. Contreras-Zárate
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  2. Andrea Niño
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  3. Liliana Rojas
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  4. Humberto Arboleda
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  5. Gonzalo Arboleda
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Correspondence to Gonzalo Arboleda.

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Contreras-Zárate, M.J., Niño, A., Rojas, L. et al. Silencing of PINK1 Inhibits Insulin-Like Growth Factor-1-Mediated Receptor Activation and Neuronal Survival. J Mol Neurosci 56, 188–197 (2015). https://doi.org/10.1007/s12031-014-0479-0

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  • DOI: https://doi.org/10.1007/s12031-014-0479-0

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