A proteomic approach to the bilirubin-induced toxicity in neuronal cells reveals a protective function of DJ-1 protein.
Unconjugated bilirubin (UCB) is a powerful antioxidant and a modulator of cell growth through the interaction with several signal transduction pathways. Although newborns develop a physiological jaundice, in case of severe hyperbilirubinemia UCB may become neurotoxic causing severe long-term neuronal damages, also known as bilirubin encephalopathy. To investigate the mechanisms of UCB-induced neuronal toxicity, we used the human neuroblastoma cell line SH-SY5Y as an in vitro model system. We verified that UCB caused cell death, in part due to oxidative stress, which leads to DNA damage and cell growth reduction. The mechanisms of cytotoxicity and cell adaptation to UCB were studied through a proteomic approach that identified differentially expressed proteins involved in cell proliferation, intracellular trafficking, protein degradation and oxidative stress response. In particular, the results indicated that cells exposed to UCB undertake an adaptive response that involves DJ-1, a multifunctional neuroprotective protein, crucial for cellular oxidative stress homeostasis. This study sheds light on the mechanisms of bilirubin-induced neurotoxicity and might help to design a strategy to prevent or ameliorate the neuronal damages leading to bilirubin encephalopathy.
Deganuto
Marta
M
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy.
Cesaratto
Laura
L
Bellarosa
Cristina
C
Calligaris
Raffaella
R
Vilotti
Sandra
S
Renzone
Giovanni
G
Foti
Rossana
R
Scaloni
Andrea
A
Gustincich
Stefano
S
Quadrifoglio
Franco
F
Tiribelli
Claudio
C
Tell
Gianluca
G
D001663:Bilirubin / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D000071617:Protein Deglycase DJ-1; D040901:Proteomics
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D001663:Bilirubin