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The locus ceruleus is among the earliest affected brain regions in Parkinson’s disease (PD) showing Lewy body pathology and neuronal loss. To improve our understanding of the pathogenesis of PD, we performed the first proteomic analysis ever of post-mortem locus ceruleus tissue of six pathologically confirmed PD patients, and six ageand gendermatched non-neurological controls. In total 2495 proteins were identified, of which 87 proteins were differentially expressed in the locus ceruleus of PD patients compared to controls. The majority of these differentially expressed proteins are known to be involved in processes that have been implicated in the pathogenesis of PD previously, including mitochondrial dysfunction, oxidative stress, protein misfolding, cytoskeleton dysregulation and inflammation. Several individual proteins were identified that have hitherto not been associated with PD, such as regucalcin, which plays a role in maintaining intracellular calcium homeostasis, and isoform 1 of kinectin, which is involved in transport of cellular components along microtubules. In addition, pathway analysis suggests a pathogenetic role for aminoacyl-tRNA-biosynthesis. These findings indicate that the proteome of the locus ceruleus of PD patients and non-neurological controls provides data that are relevant to the pathogenesis of PD, reflecting both known and potentially novel pathogenetic pathways. Karin d. van dijk1,2, Henk W. Berendse3, Benjamin drukarch1, silvina a. Fratantoni3, Thang V. Pham3, sander r. Piersma3, evelien Huisman1, John J.P. Brevé1, Henk J. Groenewegen1, Connie r. Jimenez3*, Wilma d.J. van de Berg3* 1Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands, 2Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands, 3OncoProteomics Laboratory of the Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. *Shared senior authorship Brain Pathology 2012; 22(4):485-98