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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

Polo-like kinase 2 (PLK-2) phosphorylates an unknown target, which leads to regulation of ?-synuclein mRNA by targeting exonal sequences in the gene encoding ?-synuclein, SNCA. PLK-2, and other kinases, additionally phosphorylates ?-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.

To read the article please follow this link

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