Objective: The objective of this study is to determine the expression of late cell cycle markers in Parkinson Disease (PD) and Lewy Body Dementia (LBD)

Background: Mechanisms that initiate and cause PD and LBD neuronal death are not fully understood. Several studies have shown that degenerating neurons, under certain stress conditions, can activate the program that normally guides cells to mitotic division. In these post-mitotic cells, the re-entry into the cell cycle will not end with neuron replication but with the activation of unknown mechanisms that will trigger neuronal death. Several studies have described abnormal expression of cell cycle markers in degenerating neurons. Furthermore, evidence for a completed S phase in PD brain, raises the question of what factors are missing in the adult neurons that lead to neuronal death just before the neuron enters mitosis. 

Methods: We examined 3 brains of PD, 3 brains of LBD and 3 controls brains. Sections from Substantia Nigra (SN), locus coeruleus (LC), cerebellum, frontal and temporo-occipital cortex were immunostained using antibodies against PLK1 pSer 137, PLK1 pThr210, Aurora A, cyclin B and synuclein pSer 129. Double immunofluorescence techniques against the previous markers were performed. Interactions were analyzed using proximity ligation assays.

Results: We examined the expression of Aurora A and PLK1. PLK1 is crucial to regulate mitotic entry. This event depends on Aurora-A phosphorylation of PLK1 Thr 210. Besides, dephosphorylation of PLK1 Ser-137 is required for execution of cytokinesis. PLK1 pSer 137 was upregulated in all the regions both in PD and LBD brain but no in controls. Immunoreactivity against PLK1 pThr210 was found only in the LC in the PD brains, and in the LC, cerebellum, frontal and occipital cortex in the LBD brain. No expression was found in controls. All neurons immunostained against Aurora A were also immunoreactive against PLK1 Thr-210. Cyclin B1 immunoreactivity was only circumscribed to the cytoplasm, indicating that these neurons are in a late G2 phase. Cyclin B1 immunoreactive neurons, were also PLK1 pSer 137 and PLK1 pThr210 inmunoreactive. 

Conclusions: This work describes for the first time the overexpression of two kinases involved in the G2/M transition, PLK1 and Aurora, whose over expression correlates with the severity of the pathology. These new PD targets could lead to the discovery of new pathways involved in neuronal death. 

References: Höglinger, G. U., Breunig, J. J., Depboylu, C., Rouaux, C., Michel, P. P., Alvarez-fischer, D., … Hirsch, E. C. (2007). The pRb / E2F cell-cycle pathway mediates cell death in Parkinson ’ s disease. Proceedings of the National Academy of Sciences of the United States of America, 104(9), 1–6. 

Macůrek, L., Lindqvist, A., Lim, D., Lampson, M. a, Klompmaker, R., Freire, R., … Medema, R. H. (2008). Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature, 455(7209), 119–123. 

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expression-of-late-cell-cycle-markers-in-parkinson-disease-and-lewy-body-dementia/