Ouzounoglou2014 - Modeling of alpha-synuclein effects on neuronal homeostasis

Ouzounoglou2014 - Modeling of alpha-synuclein
effects on neuronal homeostasis

This model is described in the article:

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
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.

Note: The model contains reactions of species located in different compartments. If the model is applied using volume sizes unequal to one, an extension of the model might be reasonable to guarantee mass conservation.

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