S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway

• DOI: 10.1093/brain/aws250
• Publication Date: 2012-11-20T15:18:39Z
• Authors: Kinnari Sathe; Walter Maetzler; Johannes D. Lang; Ross B. Mounsey; Corina Fleckenstein; Heather L. Martin; Claudia Schulte; Sarah Mustafa; Matthis Synofzik; Zvonimir Vukovic; Shigeyoshi Itohara; Daniela Berg; Peter Teismann
• Keywords: Male; 0301 basic medicine; metabolism [Nerve Growth Factors]; Parkinson's disease; metabolism [Tumor Necrosis Factor-alpha]; Receptor for Advanced Glycation End Products; S100B; Mice; genetics [Parkinson Disease]; blood [Parkinson Disease]; cerebrospinal fluid [Parkinson Disease]; calcium-binding protein; Gliosis; Receptors, Immunologic; metabolism [S100 Proteins]; Mice, Knockout; S100 Proteins; R; metabolism [Receptors, Immunologic]; Parkinson Disease; pathology [Gliosis]; genetics [Nerve Growth Factors]; Up-Regulation; 3. Good health; Neuroprotective Agents; S100b protein, mouse; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Female; metabolism [Neuroprotective Agents]; 570; metabolism [Parkinson Disease]; 610; S100 Calcium Binding Protein beta Subunit; R Medicine; Cell Line; 03 medical and health sciences; metabolism [Substantia Nigra]; Animals; Humans; ddc:610; Nerve Growth Factors; S100B protein, human; MPTP; pathology [Substantia Nigra]; Aged; Tumor Necrosis Factor-alpha; antagonists & inhibitors [1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine]; Original Articles; pathology [Parkinson Disease]; Mice, Inbred C57BL; Disease Models, Animal; genetics [S100 Proteins]; Case-Control Studies

Parkinson's disease is a neurodegenerative disorder that can, at least partly, be mimicked by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. S100B is a calcium-binding protein expressed in, and secreted by, astrocytes. There is increasing evidence that S100B acts as a cytokine or damage-associated molecular pattern protein not only in inflammatory but also in neurodegenerative diseases. In this study, we show that S100B protein levels were higher in post-mortem substantia nigra of patients with Parkinson's disease compared with control tissue, and cerebrospinal fluid S100B levels were higher in a large cohort of patients with Parkinson's disease compared with controls. Correspondingly, mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed upregulated S100B messenger RNA and protein levels. In turn, ablation of S100B resulted in neuroprotection, reduced microgliosis and reduced expression of both the receptor for advanced glycation endproducts and tumour necrosis factor-α. Our results demonstrate a role of S100B in the pathophysiology of Parkinson's disease. Targeting S100B may emerge as a potential treatment strategy in this disorder.