Authors:	Baeken, Marius Wilhelm
Title:	Epigenetic remodeling through a mitochondrial redox signal in an experimental model of Parkinson’s disease Epigenetische Restrukturierungen durch ein Redox-Signal mitochondriellen Ursprungs in einem experimentellen Modell der Parkinson´schen Krankheit
Online publication date:	30-Jun-2021
Year of first publication:	2021
Language:	english
Abstract:	Together with the prospect of an ever-older growing society, so will the prevalence of ageassociated neurodegenerative disorders like Parkinson's disease (PD) rise. Thus, it becomes ever more important to possess adequate means to treat and manage such malignancies. Unlike its onset, the pathophysiology of motoric deficits in PD is quite well understood these days. A precise and profound loss of dopaminergic neurons in the substantia nigra pars compacta, a mesencephalic structure, develops the well known and described symptoms of PD. One major hypothesis for the onset of PD revolves around oxidative stress created by a dysbalance in the generation and/or deetoxification of reactive oxygen species (ROS). These are usually conceived through a leakage of electrons from the respiratory complexes to molecular oxygen, which is turned into superoxide, yet rapidly transformed into non-hazardous forms by the cellular antioxidant defence system. Many models of PD, which do not follow a genetic paradigm, rely on an excessive production of ROS. One of these models, if not the most popular one, the 1-methyl-4-phenylpyridinium (MPTP/MPP +) model, was used in this work to establish the nature of epigenetic changes in dopaminergically differentiated LUHMES cells and mice. The MPTP/MPP + model relies on electron transfer disruption in the complex I of the respiratory chain, thus causing increased amounts of ROS, as well as ATP and NAD+ depletion. The strong antioxidant phenothiazine (PHT) was administered as well to survey protective effects and sever ROS mediated from metabolic stress effects. Metabolic changes this profound require the cells to adapt, which is often accompanied by epigenetic changes. This work aims to further solidify and expand the understanding of energetic, epigenetic, biochemical and molecular pathologies of PD, while also offering new treatment possibilities through the antioxidant PHT. In the PD models system, the cell's epigenome changes and is entirely turned around, while heterochromatin in form of DNA methylation appears to disappear and euchromatin markers in form of histone acetylation accumulate. Through this work all of these effects can be traced back to a loss of function of the ROS sensitive sirtuin 1 (SIRT1) and the de novo DNA methyltransferase 3B (DNMT3B). If protected by PHT, these enzymes could possibly allow the cell's chromatin to rearrange and stabilize. The epigenetic changes are accompanied by their consequential changes of transcription, especially in regard to energy acquisition by turning on the transcription of nuclear encoded mitochondrial genes. Restored chromatin may be beneficial to the process of adaptation and the cells may be able to adjust more properly to their new environment with a disabled complex I.
DDC:	570 Biowissenschaften 570 Life sciences 610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6093
URN:	urn:nbn:de:hebis:77-openscience-b0673e6b-ba25-4f09-8f3c-f712d196469a3
Version:	Original work
Publication type:	Dissertation
License:	CC BY-ND
Information on rights of use:	https://creativecommons.org/licenses/by-nd/4.0/
Extent:	XIV, 158 Seiten
Appears in collections:	JGU-Publikationen