Overview

Lewy bodies (intracellular aggregates of α-synuclein) and Lewy neurites (extracellular accumulation) are the common biomarkers of PD. They are formed by the aggregation of damaged α-synuclein, which happens when the cellular systems for protein disposal (proteasome and lysosome) cannot process all the damaged proteins. Thus, Lewy bodies and neurites formation happens when the cellular sub-systems of α-synuclein metabolism are not able to maintain a healthy balance between the production of damaged protein and their removal and recycling. These inclusion bodies have a direct implication in disease development and spreading through the brain regions, as they infer with normal cellular functioning. For example, α-synuclein aggregates can block the proteasome and affect protein production (Chen et al., 2005).

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Research

As part of the modelling of PD development, protein aggregation and Lewy bodies formation is considered (see figure). The mechanisms for Lewy bodies formation are well known, but the dynamics and regulation of such a system must be analyzed correctly, as many interactions (inhibitions, activations etc.) are present in that system (as observed by Raichur et al., 2006). The formation of α-synuclein aggregates is a triggering event that can cause further problems in the proteasome, thus perturbing the protein disposal systems from its normal, operating state. The mechanisms of aging and their effect on protein disposal must also be considered with an integrative approach, which will be possible by the use of physiological, descriptive models of the relevant cellular processes (Proctor et al., 2007).

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Contact point

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Selected References

A. Raichur, S. Vali, F. Gorin. Dynamic Modelling of α-synuclein Aggregation for the Sporadic and Genetic forms of Parkinson’s Disease. Neuroscience, 142:859-870, 2006. doi:10.1016/j.neuroscience.2006.06.052.

Q. Chen, J. Thorpe, J.N. Keller. Alpha-synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability. J. Biol. Chem., 280:30009–30017. 2005. doi:10.1074/jbc.M501308200.

C.J. Proctor, M. Tsirigotis, D.A. Gray. An In Silico Model of the Ubiquitin-Proteasome System that Incorporates Normal Homeostasis and Age-Related Decline. BMC Systems Biology, 1:17, 2007. doi:10.1186/1752-0509-1-17.

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