Doctoral Candidate Position 13 - Sulfateq BV, the Netherlands
Maintaining mitochondrial health in Parkinson's disease
Dimitrios Tantis-Tapeinos earned a BSc degree in Biology from the University of Ioannina after conduction of a thesis titled “Optimizing An In Vivo Adenoviral Model Of G2019S-LRRK2-Induced Neurodegeneration In Mice”. Subsequently he earned a MSc degree in Molecular and Clinical Neuroscience after conduction of a thesis titled “Brain-Wide Analysis of Inaccessible Memories After Sleep Deprivation for identification of underlying network-related effects”. During different internships he dealt with a variety of, distinct form classical neuroscience, fields ranging from neuroglioma proliferation control to hardware component design thus acquiring well-rounded interdisciplinary experiences.
Description of project
Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD). Variety of different genetic and environmental factors have been associated aetiologically, with increased evidence pointing to mitochondrial dysfunction as crucial pathology factor, since relevant damage can, through multiple mechanisms e.g., ATP depletion, ROS production, and neuroinflammation, lead to cellular death of Sabstantia Nigra pars compacta (SNpc) Dopamine Neurons with seemingly higher selectivity. Characteristically, post-mortem patient encephalic tissue highlighted functional impairment of Electron Transport Chain (ETC) complexes in certain PD-affected regions (Toomey et al., 2022).
Cardiolipin (CL) is a distinct phospholipid of the Inner-Mitochondrial Membrane (IMM). Under physiological conditions, approximately 15% of Cytochrome c (Cyt c) molecules are tightly bound to the IMM through hydrophobic interactions with CL, while approximately 85% of Cyt c molecules are free or loosely bound to the IMM through electrostatic interactions with CL (Santucci et al., 2019). Under PD conditions, multiple animal models have indicated alterations in synthesis, exposure to OMM, and enhanced peroxidation of CL (Fuentes et al., 2024). In contrast to loosely bound Cyt c, which acts as e- shuttle and ROS formation inhibitor, tightly bound Cyt c, which induced stereoconformational changes that facilitated the conversion of Cyt c into a Peroxidase (Hannibal et al., 2016), is involved in the oxidation of CL, destabilization of IMM & permeabilization of OMM, and initiation of apoptotic process (Shidoji et al., 1999). The current PhD project’s goals are to investigate how novel 6-chromanol-derived compounds, termed SUL compounds, mitigate the aforementioned pathology and overall mitochondrial dysfunction in PD and to elucidate the relevant pathways—e.g., mitochondrial quality control, mitochondrial homeostasis, and mitochondrially derived protein aggregation—which may be modulated.
Initially, Caenorhabditis elegans models of PD will be utilized to establish the therapeutic efficacy of the aforementioned mitochondrially-targeted SUL compounds. Assessment will incorporate: 1) Lifespan & Healthspan Measurements, 2) Motor Behaviour Evaluation, 3) Mitochondrial Potential & Respiration Monitoring, as well as 4) Determination of Levels of Oxidative Stress, Protein Aggregation, and mtDNA Damage. Subsequently, treated and untreated individuals from different strains and models will be subjected to mass spectrometry and “multiomics”-based analyses in order to identify altered, and thus possibly therapeutically-relevant, signalling pathways. Afterwards, obtained “hits” will be validated through generation of corresponding K/O and K/I Caenorhabditis elegans models, which will help determine the necessity & function, and therapy- & phenotype-manifestation capability, respectively, of identified PD-associated and SUL-associated “hits”. Finally, Caenorhabditis elegans models of PD (e.g., a-synuclein Transgenic Worms & LRRK2 Transgenic Worms) will be utilized, along with existing “multiomics” data, to investigate and uncover signalling pathways and mitochondrial mechanisms that could serve as innovational drug target for future development, thus enabling the creation of a more efficient “multi-pronged” therapeutic approach.
The aforementioned mitochondrially-targeted compounds have already shown promise in improving AD pathology (de Veij Mestdagh et al., 2022). We hypothesize that SUL-mediated enhancement of mitochondrial functionality will ultimately improve PD pathology. Overall, this work could establish proof of efficacy for PD treatment via mitochondrially-targeted compounds and could lead to the identification of novel drug targets that modulate mitochondrial fitness as potential new avenue for treating PD and related disorders.