Ceruloplasmin functional changes in Parkinson’s disease-cerebrospinal fluid

Molecular Neurodegeneration

Massimo Alessio¹  Angelo Corti⁶  Giancarlo Comi⁵  Laura Ferrari³  Maria Antonietta Volontè³  Giuseppe Magnani³  Antonio Conti¹  Massimo Lazzaro¹  Alan Zanardi⁵  Annapaola Andolfo²  Flavio Curnis⁶  Marco Barbariga⁴ 

[1] Proteome Biochemistry, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, Milan, 20132, Italy;ProMiFa-Protein Microsequencing Facility, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, Milan, 20132, Italy;INSPE-Institute of Experimental Neurology, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, Milan, 20132, Italy;Present address: Translational Neurology group, Wallenberg Neuroscience Center, BMC A10, Lund, 221 84, Sweden;Vita-Salute San Raffaele University, via Olgettina 60, Milan, 20132, Italy;Tumor Biology and Vascular Targeting, IRCCS-San Raffaele Scientific Institute, via Olgettina 60, Milan, 20132, Italy

关键词: Hydrogen peroxide;    NGR and isoDGR motif;    Ferroxidase;    Integrin-binding;    Deamidation;    Oxidative stress;    Parkinson;    Ceruloplasmin;   

Others  :  1230389
DOI  :  10.1186/s13024-015-0055-2

 received in 2015-08-28, accepted in 2015-10-29,  发布年份 2015

【 摘 要 】

Background

Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson’s disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function.

Results

We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the⁹⁶² NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSF's environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties.

Conclusions

We show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSF's pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious.

【 授权许可】

   
2015 Barbariga et al.

【 图 表 】

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