Objective: The objective is to determine the levels and interactions between PLK2  and one of its main substrates, synuclein, in the non-human primate MPTP model of Parkinson disease (PD)

Background: The molecular mechanisms leading to the loss of specific neuronal populations of dopaminergic cells have not been delineated yet in PD, but several pathogenic pathways have been identified. One of these pathways involves mitochondrial dysfunction and dysregulation of reactive oxygen species. Matsumoto and colleagues identified the PLK2 as a gene that is highly expressed in cells with defective respiration and increased oxidative stress. Furthermore, several studies have demonstrated that PLK2 can also phoshphorylate and promote selective autophagic clearance of synuclein (SCNA), the major component of Lewy bodies.

Methods: 15 Macaca fascicularis were included in the study. 10 monkeys received one weekly intravenous injection of MPTP  until they developed bilateral parkinsonian features. Animals were sacrificed and perfused with saline buffer. Punches from the Substantia Nigra (SN) and cerebellum were collected. For quantitative analysis of PLK2 and SCNA gene expression, real time PCR was performed.  Western blotting was performed using primary antibodies, against PLK2 and synuclein. 

Results: In the SN of MPTP monkeys a 1.8-fold increase was observed in the PLK2 mRNA level related to untreated monkeys. Regarding SCNA expression, we found a decrease of mRNA levels nearly to 60% compared  to untreated monkeys. Besides, both expression levels were negatively correlated (R=-0.76). In the cerebellum, no changes were detected and no correlation between the expression patterns was found (∆∆Ct=0.56±0.12).  

To evaluate if these changes were only at RNA level, we also performed Western Blot analysis. In the SN, we found a decrease of 45% in alpha-synuclein protein levels of MPTP monkeys. A fold increase of 1,5 was found in PLK2 protein level. No changes in the cerebellum were found.

Conclusions: We demonstrate for the first time that an upregulation of PLK2 exists in the brain of MPTP-monkeys, and that this upregulation is only circumscribed to the SN. Furthermore, this upregulation correlates negatively with synuclein expression, confirming previous studies that suggested the selective autophagy clearance of synuclein by PLK2 and its role in PD pathophysiology. 

References: Matsumoto, T., Wang, P.-Y., Ma, W., Sung, H. J., Matoba, S., & Hwang, P. M. (2009). Polo-like kinases mediate cell survival in mitochondrial dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14542–14546. 

Oueslati, A., Schneider, B. L., Aebischer, P., & Lashuel, H. a. (2013). Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo. Proceedings of the National Academy of Sciences of the United States of America, 110, E3945-54. 

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MDS Abstracts - https://www.mdsabstracts.org/abstract/interaction-between-plk2-polo-like-kinase-2-and-alpha-synuclein-in-the-non-human-primate-mptp-model-of-parkinson-disease/