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OJBTM
Online Journal of
Bioinformatics ©
In silico experiments on a faulty
ubiquitin-proteasome system in the pathogenesis of Parkinson’s disease
Paola Lecca
Microsoft Research -
ABSTRACT
Lecca P, In silico experiments on a faulty
ubiquitin-proteasome system in the pathogenesis
of Parkinson’s disease, Onl J Bioinform.,
9 (1):30-43, 2008. A growing body of evidence suggests
that the accumulation of misfolded proteins in brain tissues is a crucial event
in the Parkinson’s disease neurodegeneration. Both pathogenic genetic mutations
and the exposure to environmental toxins may induce abnormal protein
conformations or compromise the ability of the cellular machinery (mainly the
chaperones and ubiquitin-proteasome systems) to detect and degrade misfolded
proteins. Although the recent explosion in the rate of discovery of genetic
defects and environmental factors linked to Parkinson’s disease (PD) have
provided tangible clues to the neurobiology of the disorder, they have provided
neither direct explanation for the disease process or its key biochemical
mechanism. The aim of the work is to provide computational models for in silico
experiments, that can enable the medical researchers to
formulate new hypotheses for elucidating some important and still elusive
aspects of the Parkinson’s disease and for designing new wet experiments
to test them. Here we present three stochastic models of a faulty mechanism of
protein re-folding and degradation of misfolded proteins: (i)
a model describing the effects of environmental stress factors on the
processing of misfolded proteins, and (ii) two models of genetic Parkinson due
to the mutations of α-synuclein and parkin. Our models are specified in biochemical stochastic
π-calculus and are based on what is currently known about the genetic
mutations and environmental stress causing PD. The expressive capabilities of
this formalism in the description of parallel and competitive nature of
biochemical interactions make it particularly suitable for modeling the
intricate mechanism of proteins folding, re-folding and eventually degradation.
Furthermore, the simulation results point out those kinetic quantitative
parameters (e. g. reaction rate coefficients and the number of available
chaperons), whose variations lead to significant
changes in the capability of the system to react to the accumulation of
dangerous proteins.
Keywords:
stochastic π-calculus, kinetic analysis, Parkinson’s disease, parkin, ubiquitin, chaperones.
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