Pathogenic Mechanisms and Therapeutic Opportunities in Parkinson’s Disease: A Molecular and Spatial Perspective

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuronal loss and α-synuclein accumulation. Despite extensive research, the spatial and molecular basis of selective neuronal vulnerability and therapeutic modulation remains unclear. This dissertation addresses two critical gaps: (1) the lack of spatially resolved insight into cellular responses to neurodegeneration, and (2) the need for therapeutic strategies targeting α-synuclein pathology. In the first part of this study, we constructed a high-resolution molecular atlas of PD-related neurodegeneration by integrating single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics in a 6-hydroxydopamine (6-OHDA) rat model. We identified 22 transcriptionally distinct cell types and discovered compensatory expansion of specific glutamatergic neurons and a previously uncharacterized Asic2⁺ dopaminergic subtype. Cell– cell interaction analyses revealed an imbalance between stress-inducing (CypA-associated) and neuroprotective (PSAP-mediated) signaling pathways, particularly in Asic2⁺ neurons. These findings provide a spatially resolved framework for understanding glial–neuronal coordination in PD and identify candidate signaling pathways contributing to selective vulnerability. The second part of the dissertation investigates ceramide metabolism as a pathogenic and therapeutic axis in PD. Lipidomic profiling of postmortem midbrain tissue revealed elevated levels of long-chain ceramide species in PD and Lewy body dementia (LBD). Transcriptomic analyses of patient-derived dopaminergic neurons and glial cells confirmed upregulation of genes involved in ceramide biosynthesis and concomitant suppression of mitophagy pathways. Using cellular, animal, and human-derived organoid models, we demonstrate that pharmacological inhibition of de novo ceramide synthesis via myriocin reduces α-synuclein aggregation, restores mitophagy, and rescues motor and cognitive impairments in A53T transgenic mice. Transcriptomic normalization following myriocin treatment revealed downregulation of pro-inflammatory mediators and upregulation of genes associated with synaptic transmission, mitochondrial homeostasis, and neuronal plasticity. Together, these studies advance a dual perspective on PD pathogenesis by elucidating spatially organized cellular responses to dopaminergic injury and establishing ceramide metabolism as a modifiable pathway for therapeutic intervention. The integrated findings contribute to a deeper understanding of PD pathobiology and support the development of spatially informed and mechanism-targeted treatments.