Poul Henning Jensen's group publish finding of novel pathway regulating α-synuclein levels in brain

The title of the paper is: Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production

2017.08.09 | Maria Thykær Jensen

Polo-like kinase 2 (PLK-2) phosphorylates an unknown target, which leads to regulation of α-synuclein mRNA by targeting exonal sequences in the gene encoding α-synuclein, SNCA. PLK-2, and other kinases, additionally phosphorylates α-synuclein, which might be involved in the misfolding of the protein and development of toxic protein species such as oligomers and fibrils.

This article investigates the Polo-like kinase 2 (PLK-2) mediated regulation of α-synuclein, a key protein in the development of Parkinson's disease. The ability to decrease α-synuclein levels holds great promise as a treatment for Parkinson's disease, and this paper search for new strategies to obtain this, by investigating the underlying pathway of the PLK-2 mediated regulation of α-synuclein. 2 key findings are presented: 1. The PLK-2 mediated regulation of α-synuclein levels and the phosphorylation at Serine 129 are not connected as previously suggested, but are two independent mechanisms. 2. Inhibition of PLK-2 increases α-synuclein in cells and in vivo by increasing expression of α-synuclein mRNA. The paper describes a novel pathway regulating α-synuclein mRNA, and shows that PLK-2 does not, as previously suggested, regulate α-synuclein through phosphorylation and autophagic degradation, but rather by increase α-synuclein mRNA production. Today, no small molecule drug targets are known to decrease α-synuclein levels, but this work lays the ground for further investigations of the PLK-2 dependent pathway, to search for suitable targets that can be modulated to decrease α-synuclein and hereby hopefully provide disease modifying treatment for Parkinson's disease.

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Rikke H. Kofoed (1), Jin Zheng (1), Nelson Ferreira (1), Søren Lykke-Andersen (2), Mauro Salvi (3), Cristine Betzer (1), Lasse Reimer (1), Torben Heick Jensen (2), Karina Fog (4), Poul H. Jensen (1)

1 Aarhus University, DANDRITE – Danish Research Institute of Translational Neuroscience, Dept. of Biomedicine, OleWorms Allé 3, DK-8000 Aarhus, Denmark 

2 Aarhus University, Dept. of Molecular Biology and Genetics, C.F. Møllers Allé 3, DK-8000 Aarhus, Denmark 

3 University of Padova, Dept. of Biomedical Sciences, Via U. Bassi 58/B, I-35131, Padova, Italy 

4 H. Lundbeck A/S, Neurodegeneration & Biologics, Ottiliavej, DK-2500, Copenhagen, Denmark

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