Publication date: Feb 11, 2020
Parkinson’s disease (PD) is considered to be the second most common progressive neurodegenerative brain disorder after Alzheimer’s disease, which is caused by misfolding and aggregation of Alpha-synuclein (?-synuclein). It is characterized by distinct aggregated fibrillary form of ?-synuclein known as the Lewy bodies and Lewy neurites. The most promising approach to combat PD is to prevent the misfolding and subsequent aggregation of ?-synuclein. Recently, Oleuropein aglycone (OleA) has been reported to stabilize the monomeric structure of ?-synuclein, subsequently favoring the growth of non-toxic aggregates. Therefore, understanding the conformational dynamics of ?-synuclein monomer in presence of OleA is significant. Here, we have investigated the effect of OleA on the conformational dynamics and the aggregation propensity of ?-synuclein using molecular dynamics simulation. From MD trajectory analysis, we noticed that when OleA is bound to ?-synuclein, the intramolecular distance between non-amyloid-? component (NAC) domain and C-terminal domain of ?-synuclein was increased, while long-range hydrophobic interactions between the two region was reduced. OleA was found to interact with the N-terminal domain of ?-synuclein, making this region unavailable for interaction with membranes and lipids for the formation of cellular toxic aggregates. From the binding free energy (BFE) analysis, we found binding affinity between ?-synuclein and OleA to be indeed high (?G = -12.56?kcal mol from MM-PBSA and ?G = -27.41?kcal molfrom MM-GBSA). Our findings in this study thus substantiate the effect of OleA on the structure and stabilization of ?-synuclein monomer that subsequently favors growth of stable and non-toxic aggregates.
- Amyloid aggregates of the deubiquitinase OTUB1 are neurotoxic, suggesting that they contribute to the development of Parkinson’s disease.
- The molecular chaperone β-casein prevents amorphous and fibrillar aggregation of α-lactalbumin by stabilisation of dynamic disorder.
- Scutellarin Inhibits the Uninduced and Metal-Induced Aggregation of ɑ-Synuclein and Disaggregates Preformed Fibrils: Implications for Parkinson’s disease.
- The N-terminal Acetylation of α-Synuclein Changes the Affinity for Lipid Membranes but not the Structural Properties of the Bound State.
- Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate.
- Synucleinopathies: Where we are and where we need to go.