Ouzounoglou et al., (2014). Modeling of alpha-synuclein effects on neuronal homeostasis.
March 2015, model of the month by Audald Lloret-Villas
Original model: BIOMD0000000559
Parkinson's disease (PD) is a degenerative disorder of the central nervous system caused by the selective loss of dopaminergic neurons in the substantia nigra. A central pathological hallmark of PD is the formation of Lewy bodies, within which there accumulate aggregated proteins. The main components of the inclusion bodies are aggregates of the protein alpha-synuclein (ASYN) , a 140 amino acid pre-synaptic peptide. The overexpression of ASYN gene (SNCE) has been suggested to contribute to the development of PD .
Soluble oligomers of ASYN, rather than insoluble and fully fibrillar forms, are considered the toxic species that lead to cell death.The potential modification of ASYN by dopamine (DA) inhibits the formation of fibrils and the aggregation of the protein, and triggers the accumulation of soluble oligomers. Furthermore, this modification has been found to have causal role in the inhibition of the main pathways of ASYN degradation: Chaperone mediated autophagy (CMA), macroautophagy and proteasome degradation (Figure 1). DA-mediated modification of ASYN may have a central role in the induction of cellular death and, therefore, in neurodegeneration.
Figure 1ASYN degradation pathways. ASYN degradation is known to occur by he following pathways: (I) In chaperone-mediated autophagy (CMA), monomers and dimers bind to lyposomal-associated membrane protein 2a (Lamp2a) and either continue to oligomerize or undergo degradation within the lysosome. DA-modified monomers bind to Lamp2a but oligomerize without entering, causing an aberrant occupation of the receptor which inhibits the normal function of CMA .(II) In macroautophagy, species up to oligomers of wild type (WT) and modified ASYN are degraded by autophagosomes.(III) In proteasome proteolysis, oligomers of ASYN (trimers to nonamers) are targeted for degradation by proteasomes. Proteasome impairments are the result of oligomer over-occupation and higher molecular weight species of ASYN.Non-modified WT ASYN can form aggregates whilst DA-modified ASYN forms complexes up to nonamers (toxic oligomeric species). Figure from 
A biomolecular reaction model describing the intracellular dynamics of ASYN was developed by Ouzounoglou et al., (2014) [5, BIOMD0000000559]. It focusses on ASYN dynamics in relation to overexpression, post-translational modification, oligomerization and the fundamental lysosomal and proteasomal degradation pathways, as well as the modifications conferred by DA. The calibrated model agrees with experimental evidence and allows qualitative estimation of the protein levels that are capable of deregulating proteolytic homeostasis.
Figure 2Average output curves of ten stochastic simulations of the model. This figure illustrates time course dynamics of alpha-synuclein on neuronal homeostasis: several species are simulated and compared to experimental results. panels A and B show different scales. Figure from 
Initially, a time course simulation was performed using conditions determined from previous experimental results, many of them taken from Proctor et al., (2010) [6, BIOMD0000000293] and parameter estimations. Figure 2 shows the dynamics of central species of the model during 7 days. Fluctuations in the free lyposomal-associated membrane protein 2a (Lamp2a) levels indicate that the repression of CMA activity is due to two parallel processes: gradual reduction of the levels of free Lamp2a and over-occupation of the remaining receptors. High molecular weight species of ASYN remain at low levels, significantly below the levels of dimers and oligomers.
Three different biological scenarios were tested (Figure 3) in order to simulate the alteration of ASYN dynamics through by changes of relevant parameters:
- In Figures 3A and 3B, where production rate of ASYN is reduced by 50%, the levels of dimers and oligomers (green and red lines, respectively) are found to be significantly lower compared to the base model. The levels of these species may be reduced because of the higher amount of free Lamp2a (blue lines).
- When the initial amount of Lamp2a is tripled, in Figures 3C and 3D, the concentration of this protein is significantly superior to zero during the whole simulation. Final rates of dimers and oligomers are lower than those at day 0.
- In the last case (Figures 3E and 3F) DA production is completely cut off. The plot predicts a return of dimers to their initial levels, slight degradation of oligomers and presence of free Lamp2a receptors at the end of the simulation. An interesting feature is the increased levels of higher molecular weight ASYN species, the hypothetical result of exclusive oligomerization of ASYN by the non-modified pathway.
Figure 3Model prediction testing different hypothetical scenarios. This figure displays the simulation of alpha-synuclein dynamics on three different initial conditions discussed in detail in Results: halved production rate of ASYN (3A and 3B), triplication of Lamp2a receptor levels in the lysosome (3C and 3D), and cut-off of dopamine production (3E and 3F). Panels on the left and on the right show different scales. Figure from 
A holistic biomolecular reaction model that successfully recapitulates the dynamic phenomena of ASYN dynamics and predicts the biological system's behaviour for a number of in silico intervention is described here. This biomodel, specially targeting the role of DA and its interactions, predicted and increased cell survival probability in three hypothesised intervention scenarios: halved production rate of ASYN, triplication of Lamp2a receptor levels in the lysosome, and cut-off of dopamine production. Potential next steps could include an extension of the model with cell death related pathways as well as ASYN secretion and uptake from neighbouring neurons.
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