Project title
Computational Studies of Parkinson’s Diseases
Collaborators and funding
Federation University Australia
Contact(s)
- Jiapu Zhang, Federation University Australia, j.zhang@federation.edu.au
Project description and aims
Parkinson’s disease (PD), the second most common neurodegenerative disorder in human, was first described as the “shaking palsy” in 1817 (now being the fastest growing neurodegenerative condition in the world) by the English doctor James Parkinson, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. As the disease worsens, non-motor symptoms become increasingly common. The symptoms generally come on slowly over time. Early in the disease, the most obvious are shaking, rigidity, slowness of movement, and difficulty with walking. Thinking and behavioral problems may also occur. Dementia becomes common in the advanced stages of the disease. Depression and anxiety are also common, occurring in more than a third of people with PD. Other symptoms include sensory, sleep, and emotional problems. The exact cause of these symptoms is not yet fully understood and currently there is no cure to PD.
PD has no single cause, with links to several gene mutations as well as environmental influences. The cause of PD is generally unknown, but believed to involve genetic factors: those with a family member affected are more likely to get the disease themselves. Around 15% of individuals with PD have a first-degree relative who has the disease, and 5-10% of people with PD are known to have forms of the disease that occur because of a mutation in one of several specific genes. The role of genetic factors in the pathogenesis of PD has received increasing attention from scholars. Since the discovery of the first PD-causing gene alpha-synuclein SNCA in the late 1990s, at least 6 pathogenic genes have been associated with familial PD. Genetic factors are also only one of the factors in the pathogenesis of PD. alpha-synuclein (aS) is the main component of the Lewy bodies that accumulate in the brains of people with PD. Misfolding of the protein aS, which associates with presynaptic vesicles (aS is typically found in the presynaptic terminals of neurons, where it plays a role in synaptic transmission and synaptic vesicle transport), has been implicated in the molecular chain of events leading to PD. aS can exist in different conformations, including an unstructured or unfolded form in the cytosol and a helical form associated with lipid membranes. Part I of this book studies full-length wild-type aS proteins (aS 1-140) and their (about eight) mutants from the optimized molecular structure and Molecular Dynamics (MD) structural dynamics points of view. We will study the effects of point mutations and other factors on the distribution of conformers in aS. As we all know aS protein is not completely disordered. We may use variants of the protein that have been shown to have a range of effects in experimental animals or tissue culture. The most important is how point mutations can cause such a big influence on conformer distribution and in turn how can this lead to such a diversity of biological effects. In this project our systematic MD study of a wider range of mutants (including these at least 6 pathological mutants, A30P, E35K, 4E6K, H50Q, G51D, A53T, A53T-V40D-V74D, E57K) with experimentally determined conformer distributions and known biological properties would provide some answers.
To do extensive MD-studies of the full length aS(1-140) WT and its at least 6 mutants, we will do under different force fields such as the ff03-AMBER force field, the DES-Amber force field, the a99SB-disp force field, the ff14SBonlysc force field, the GB99dms force field, the CHARMM36m force field, the SIRAH force field, etc.
How is ABLeS supporting this work?
This work is supported through the Production Bioinformatics scheme provided by ABLeS. The support includes storage and compute allocation.
Expected outputs enabled by participation in ABLeS
The research results will be published by a Springer Nature monograph or several journals’ articles.
These details have been provided by project members at project initiation. For more information on the project, please consult the contact(s) or project links above.