Brain Inflammaging in Parkinson's Disease

Aging is the primary risk factor for Parkinson’s disease (PD) and is accompanied by a chronic, low-grade inflammatory state known as inflammaging. In the central nervous system, microglia are key mediators of neuroinflammation and can shift with age toward primed or dysfunctional states that may contribute to neurodegeneration. This thesis investigates the contribution of brain inflammaging to PD, with a specific focus on immune-related mechanisms linked to LRRK2, the most common genetic cause of familial PD and a broader modulator of immune responses. The thesis is divided into six chapters which reflect self-standing but cohesive subprojects. Some are already in the form of publications (Chapter I and II), while others are manuscripts in preparation (Chapter IV, V and VI) Chapter I provides the conceptual framework by reviewing how microglial aging impacts neurodegenerative diseases, with emphasis on PD-related pathways such as cytokine dysregulation, impaired phagocytosis, and interactions with α-synuclein pathology. Chapter II, presented in published form, examines inflammasome-related mechanisms in microglia, showing that the inflammasome adaptor protein ASC aggregates in microglial nuclei during inflammasome priming, a phenotype which is exacerbated in LRRK2-G2019S PD, supporting a role for LRRK2 in modulating inflammatory signaling. Chapter III documents the optimization and limitations of approaches aimed at profiling the LRRK2 interactome in microglia under inflammatory stimulation, providing methodological insights for future studies. Chapter IV involves the investigation of a whole-blood transcriptomics dataset from the PPMI cohort to assess age-related gene expression changes in idiopathic PD and healthy controls, integrating differential expression with curated LRRK2 interaction networks and functional enrichment analyses. Chapter V evaluates LRRK2 expression patterns in the aging human brain using single-nucleus RNA sequencing and pseudobulk differential expression, and further characterizes microglial 3 transcriptional programs across age groups using high-dimensional co-expression network analysis. Finally, Chapter VI compares human and mouse LRRK2 structural and interactome-related features in silico to highlight species-specific differences that may influence translational interpretation of LRRK2 biology. Overall, this work supports the view that aging-associated immune remodeling intersects with PD risk mechanisms and provides a multi-layered framework to study LRRK2-linked inflammatory pathways across peripheral and central immune compartments.