ETD

• bioinformatics
• biology
• computer science
• dopaminergic damage
• dopaminergic neurons
• informatics
• kisspeptins
• neurobiology
• neuroprotection
• parkinson's disease
• peptides
• single-cell transcriptomics
• systems biology

The thesis investigates the emerging neuroprotective potential of kisspeptins, particularly KP-54 and its receptor KISS1R, in Parkinson's disease. Dopaminergic neurons exhibit an intrinsic vulnerability to mitochondrial dysfunction, oxidative stress, and impaired protein homeostasis, motivating the investigation of endogenous signaling pathways potentially involved in neuronal survival. The research adopts a systems biology approach integrating single-nucleus transcriptomics, differential gene expression, and causal network reconstruction. Following an exploratory assessment of murine models, the study focuses on human postmortem brain data to investigate molecular mechanisms within distinct dopaminergic populations. High-resolution reference-based annotation identifies three neuronal subpopulations, characterized by different degrees of vulnerability and resilience. Due to the sparse expression of KISS1R, a functional proxy combining receptor detection with GNAQ and selected phenotypic markers is developed to distinguish KISS1R-associated transcriptional states. Subsequent pseudobulk analyses reveal alterations in pathways associated with mitochondrial regulation, proteostasis, cellular stress, and autophagy. Transcription factor activities inferred through DoRothEA are integrated into CARNIVAL causal network models, exploring alternative KISS1R signaling states and their potential downstream effects. The reconstructed networks suggest candidate regulatory connections involving EGFR, MAPK signaling, and protein quality control mechanisms. Rather than establishing direct neuroprotection, the study identifies molecular signatures and potential signaling routes that could guide future experimental validation of KISS1R-mediated dopaminergic resilience.