In silico modeling of the effects of alpha-synuclein oligomerization on dopaminergic neuronal homeostasis

BMC Systems Biology

Elias S Manolakos²  Kostas Vekrellis¹  Leonidas Stefanis⁵  Maria Xilouri¹  Evangelia Emmanouilidou¹  Dimitrios Kalamatianos³  Eleftherios Ouzounoglou⁴ 

[1] Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou, Athens 11527, Greece;Department of Informatics and Telecommunications, Graduate Program “Information Technologies in Medicine and Biology”, National and Kapodistrian University of Athens, Athens 15784, Greece;Division of Developmental Biology, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou, Athens 11527, Greece;In Silico Oncology Group, Laboratory of Microwaves and Fiber Optics, Institute of Communication and Computer Systems, School of Electrical and Computer Engineering, National Technical University of Athens, 9 Iroon Polytechniou, Zografou, 15780 Athens, Greece;Second Department of Neurology, University of Athens Medical School, Athens, Greece

关键词: In silico experiments;    Biomolecular reaction networks modeling;    Neurodegeneration;    Alpha-synuclein;    Parkinson’s disease;   

Others  :  866395
DOI  :  10.1186/1752-0509-8-54

 received in 2013-11-04, accepted in 2014-04-22,  发布年份 2014

【 摘 要 】

Background

Alpha-synuclein (ASYN) is central in Parkinson’s disease (PD) pathogenesis. Converging pieces of evidence suggest that the levels of ASYN expression play a critical role in both familial and sporadic Parkinson’s disease. ASYN fibrils are the main component of inclusions called Lewy Bodies (LBs) which are found mainly in the surviving neurons of the substantia nigra. Despite the accumulated knowledge regarding the involvement of ASYN in molecular mechanisms underlying the development of PD, there is much information missing which prevents understanding the causes of the disease and how to stop its progression.

Results

Using a Systems Biology approach, we develop a biomolecular reactions model that describes the intracellular ASYN dynamics in relation to overexpression, post-translational modification, oligomerization and degradation of the protein. Especially for the proteolysis of ASYN, the model takes into account the biological knowledge regarding the contribution of Chaperone Mediated Autophagy (CMA), macro-autophagic and proteasome pathways in the protein’s degradation. Importantly, inhibitory phenomena, caused by ASYN, concerning CMA (more specifically the lysosomal-associated membrane protein 2a, abbreviated as Lamp2a receptor, which is the rate limiting step of CMA) and the proteasome are carefully modeled. The model is validated by simulation studies of known experimental overexpression data from SH-SY5Y cells and the unknown model parameters are estimated either computationally or by experimental fitting. The calibrated model is then tested under three hypothetical intervention scenarios and in all cases predicts increased cell viability that agrees with experimental evidence. The biomodel has been annotated and is made available in SBML format.

Conclusions

The mathematical model presented here successfully simulates the dynamic phenomena of ASYN overexpression and oligomerization and predicts the biological system’s behavior in a number of scenarios not used for model calibration. It allows, for the first time, to qualitatively estimate the protein levels that are capable of deregulating proteolytic homeostasis. In addition, it can help form new hypotheses for intervention that could be tested experimentally.

【 授权许可】

   
2014 Ouzounoglou et al.; licensee BioMed Central Ltd.

【 图 表 】

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