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Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis

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Short description
Abstract:

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.
Format
SBML (L2V4)
Related Publication
  • In silico modeling of the effects of alpha-synuclein oligomerization on dopaminergic neuronal homeostasis.
  • Ouzounoglou E, Kalamatianos D, Emmanouilidou E, Xilouri M, Stefanis L, Vekrellis K, Manolakos ES.
  • BMC Syst Biol 2014; 8: 54 , 0/ 2014 , Volume 8 , pages: 54
  • 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.
Contributors
Eleftherios Ouzounoglou, administrator

Metadata information

Curation status
Curated
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Model files

BIOMD0000000559.xml.origin SBML L2V4 representation of Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis 466.99 KB Preview | Download

Additional files

Ouzounoglou2014.cps Copasi file of the model 572.16 KB Preview | Download

  • Model originally submitted by : Eleftherios Ouzounoglou
  • Submitted: Dec 1, 2014 10:06:53 PM
  • Last Modified: Dec 21, 2018 5:53:03 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Dec 21, 2018 5:53:03 PM
    • Submitted by: administrator
    • With comment: Include the additional files provided by the submitter in the original submission: Ouzounoglou2014.cps
  • Version: 2 public model Download this version
    • Submitted on: Apr 8, 2016 6:44:36 PM
    • Submitted by: Eleftherios Ouzounoglou
    • With comment: Current version of Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis
  • Version: 1 public model Download this version
    • Submitted on: Dec 1, 2014 10:06:53 PM
    • Submitted by: Eleftherios Ouzounoglou
    • With comment: Original import of Ouzounoglou2014 - ASYN Oligomers_Lamp2a Inhibition_Neurodegeneration
Curator's comment:
(added: 09 Dec 2014, 14:42:40, updated: 09 Dec 2014, 14:42:40)
Figure 7 of Supplementary material 5 (derived from Figure 5 of the reference publication) has been reproduced here. Dynamics of several alpha-synuclein conformations are simulated during 7 days (600000 seconds). The simulation was done using SBML odeSolver. The plot were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link: