Epigenetic remodeling through a mitochondrial redox signal in an experimental model of Parkinson’s disease
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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.