The Locus coeruleus in Parkinson’s disease - from basic research to new translational perspectives -

This cumulative dissertation summarizes three peer-reviewed publications addressing different aspects of the prodromal and manifest phase of Parkinson’s disease with special emphasis on the vulnerability of the noradrenergic locus coeruleus. The first publication represents an original article describing the establishment and characterization of the first ever α-synuclein overexpression mouse model for the locus coeruleus. Narrative articles two and three discuss the importance of the locus coeruleus in context of prodromal Parkinson’s disease, and the heterogeneity of the affected mesencephalic and extramesencephalic dopaminergic systems in manifest Parkinson’s disease. The first publication entitled “A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson’s disease-like pathology in neurons and glia” describes the establishment of the first locus coeruleus α-synucleinopathy mouse model. The data show that viral vector mediated focal overexpression of human A53T-α-synuclein triggered time-dependent neurodegeneration of noradrenergic locus coeruleus neurons, accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglial cells and induction of progressive micro- and astrogliosis. Apart from this local pathology, we observed abundant α-synuclein positive axons in LC output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. The second publication entitled “The locus coeruleus – another vulnerability target in Parkinson’s disease” addresses the role of the locus coeruleus noradrenergic system in prodromal and manifest Parkinson’s disease. Within this review we provide a comprehensive description of the neuroanatomical basis of the locus coeruleus system and its implication in Parkinson’s disease, summarize highly relevant vulnerability factors, and list all animal studies conducted so far investigating locus coeruleus pathology in experimental research. Further, we provide a therapeutic outlook on how noradrenergic replacement therapy has already been successfully tested in manifest Parkinson’s disease patients and how locus coeruleus dysfunction can be of use for the development of disease modifying therapy approaches and disease progression biomarkers. Within the third publication entitled “Mesencephalic and extramesencephalic dopaminergic systems in Parkinson’s disease”, we provide a historical overview over the key milestones of Parkinson’s disease pathogenesis and therapy, dissect the dopaminergic basis of the cardinal parkinsonian motor symptomatology, summarize the anatomical features of the ten dopaminergic systems of the mammalian central nervous system and their involvement in Parkinson’s disease, illustrate how the advanced dopaminergic imaging techniques contribute to optimized differential diagnosis and pathogenetic knowledge, and explain how dopaminergic replacement therapy improves the cardinal motor symptomatology while simultaneously inducing a new set of symptoms based on a hyperdopaminergic status