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Psychological Stress Phenocopies Brain Mitochondrial Dysfunction and Motor Deficits as Observed in a Parkinsonian Rat Model

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Abstract

Psychological distress is a public health issue as it contributes to the development of human diseases including neuropathologies. Parkinson’s disease (PD), a chronic, progressive neurodegenerative disorder, is caused by multiple factors including aging, mitochondrial dysfunction, and/or stressors. In PD, a substantial loss of substantia nigra (SN) neurons leads to rigid tremors, bradykinesia, and chronic fatigue. Several studies have reported that the hypothalamic-pituitary-adrenal (HPA) axis is altered in PD patients, leading to an increase level of cortisol which contributes to neurodegeneration and oxidative stress. We hypothesized that chronic psychological distress induces PD-like symptoms and promotes neurodegeneration in wild-type (WT) rats and exacerbates PD pathology in PINK1 knockout (KO) rats, a well-validated animal model of PD. We measured the bioenergetics profile (oxidative phosphorylation and glycolysis) in the brain by employing an XF24e Seahorse Extracellular Flux Analyzer in young rats subjected to predator-induced psychological distress. In addition, we analyzed anxiety-like behavior, motor function, expression of antioxidant enzymes, mitochondrial content, and neurotrophic factors brain-derived neurotrophic factor (BDNF) in the brain. Overall, we observed that psychological distress diminished up to 50% of mitochondrial respiration and glycolysis in the prefrontal cortex (PFC) derived from both WT and PINK1-KO rats. Mechanistically, the level of antioxidant proteins, mitochondrial content, and BDNF was significantly altered. Finally, psychological distress robustly induced anxiety and Parkinsonian symptoms in WT rats and accelerated certain symptoms of PD in PINK1-KO rats. For the first time, our collective data suggest that psychological distress can phenocopy several aspects of PD neuropathology, disrupt brain energy production, as well as induce ataxia-like behavior.

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Data Availability

All data of this study are available from the corresponding authors.

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Acknowledgments

We thank Drs. Robert Renden, Ángel G. Diaz-Sanchez, and Gilberto Mercado Mercado for their valuable technical support and constructive criticisms.

Funding

This study was funded by the Pennington Foundation (Nevada), by National Institutes of Health (NIH) grant R01 NS105783, and by Consejo Nacional de Ciencia y Tecnología (CONACYT) 254483, 2833, and MG-fellowship by CONACYT.

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Authors and Affiliations

  1. Department of Pharmacology, Reno School of Medicine, University of Nevada, Reno, NV, 89557, USA

    Mariana Grigoruţă, Raul Y. Dagda & Ruben K. Dagda

  2. Departamento de Ciencias Químico Biológicas, Universidad Autónoma de Ciudad Juárez, Anillo envolvente Pronaf y Estocolmo s/n, 32310, Ciudad Juarez, Mexico

    Mariana Grigoruţă & Alejandro Martínez-Martínez

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  1. Mariana Grigoruţă
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GM performed the experiments. GM, DRK, MMA and DRY designed the study. DRY provided technical assistance. GM, DRK and MMA analyzed the data and wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Alejandro Martínez-Martínez or Ruben K. Dagda.

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All animal experiments were performed according the ARRIVE guidelines and by using an animal protocol (#572) that was approved by the IACUC at the University of Nevada, Reno, USA.

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7-month PINK1-KO rats show sever motor disfunction (a) grip strength of hindlimbs, (b) number of hindlimbs slips in the 2 cm beam balance, n = 8 WT rats and 15 PINK1-KO rats. Data are mean ± SEM. *p ≤ 0.05, **p ≤ 0.01, unpaired t-test. (PNG 113 kb)

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Grigoruţă, M., Martínez-Martínez, A., Dagda, R.Y. et al. Psychological Stress Phenocopies Brain Mitochondrial Dysfunction and Motor Deficits as Observed in a Parkinsonian Rat Model. Mol Neurobiol 57, 1781–1798 (2020). https://doi.org/10.1007/s12035-019-01838-9

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