1) The BCL2 code to dopaminergic development and Parkinson's disease
Currently, there is no real cure for Parkinson's disease (PD), the second most common neurodegenerative disorder. Attenuating the rate of cell death would obviously be beneficial for PD patients, and key to understanding why dopaminergic neurons in the Substantia Nigra compacta (SNc) degenerate is understanding the genetic makeup that causes this predisposition. The answer may lie in the embryonic development of dopaminergic neurons in the SNc, which is coordinated by a multitude of both transcription and growth factors. This developmental program generates such a diversity that one could say that every adult neuron has its own identity and one cannot substitute for another. However, a major common denominator of developing dopaminergic neurons is that they undergo cell death when key transcription factors or growth factors are absent. We propose that these key transcription factors and growth factors control the expression of BCL2 proteins, proteins which directly control the balance between neuronal survival and death. By hijacking the BCL2 system controlling neuronal survival and death, neurodegeneration in PD may be therapeutically prevented and is the penultimate goal of this study.
By using a Parkinson's disease mouse model and state of the art techniques we will identify the BCL2 factors expressed in dopaminergic neurons of the SNc and examine their individual contribution to neuronal survival. By manipulating the levels of the identified BCL2 factors and their upstream regulators we will identify novel targets to enhance dopaminergic viability which may serve as novel candidates for therapeutic intervention.
Douma, E. H., Stoop, J., Lingl, M. V. R., Smidt, M. P., & van der Heide, L. P. (2024). Phosphodiesterase inhibition and Gucy2C activation enhance tyrosine hydroxylase Ser40 phosphorylation and improve 6-hydroxydopamine-induced motor deficits. Cell and Bioscience, 14, Article 132.