α-Synuclein Misfolding Versus Aggregation Relevance to Parkinson’s Disease: Critical Assessment and Modeling

Abstract

α-Synuclein, an abundant and conserved presynaptic brain protein, is implicated as a critical factor in Parkinson's disease (PD). The aggregation of α-synuclein is believed to be a critical event in the disease process. α-Synuclein is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. Therefore, it is classified as an "intrinsically disordered protein." Recently, a debate has challenged the view on the intrinsically disordered behavior of α-synuclein in the cell. It has been proposed that α-synuclein is a stable tetramer with a low propensity for aggregation; however, its destabilization leads to protein misfolding and its aggregation kinetics. In our critical analysis, we discussed about major issues: (i) why α-synuclein conformational behavior does not fit into the normal secondary structural characteristics of proteins, (ii) potential amino acids involved in the complexity of misfolding in α-synuclein that leads to aggregation, and (iii) the role of metals in misfolding and aggregation. To evaluate the above critical issues, we developed bioinformatics models related to secondary and tertiary conformations, Ramachandran plot, free energy change, intrinsic disordered prediction, solvent accessibility, and FoldIndex pattern. To the best of our knowledge, this is a novel critical assessment to understand the misfolding biology of synuclein and its relevance to Parkinson's disease.

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

“…The aggregation of αS is closely related to several neurodegenerative diseases including Parkinson’s disease (PD) [1, 3]. Recently it was found that αS was present in aggregates of the Krabbe disease and apparently prone to fibrillization in the presence of psychosine [4].…”

“…αS adopts different conformations under various environments. Under physiological conditions, αS is characterized as an intrinsically disordered protein, exhibiting a random coil conformation in aqueous solution [3]. In the presence of the membrane, αS displays an α-helical secondary structure as observed from solution NMR structure of micelle-bound αS [5, 6].…”

“…In the presence of the membrane, αS displays an α-helical secondary structure as observed from solution NMR structure of micelle-bound αS [5, 6]. Full-length αS can be divided into three distinct domains, the N-terminal domain (residues 1–60) which is amphipathic and responsible for binding to phospholipids [7]; the non-amyloid-β component (NAC) domain (residues 61–95) which is highly hydrophobic and assumed to be essential for αS aggregation [3, 8], and the acidic negatively charged C-terminal domain (residues 96–140) believed to be critical for the chaperone-like activity of αS [9, 10]. The self-assembly of αS is accompanied by conformational transitions [11]; however, the molecular mechanism remains largely unknown partly due to the lack of molecular structures of αS aggregates.…”

Combination therapies: The next logical Step for the treatment of synucleinopathies?

“…However, given that this protein is involved in normal synaptic transmission, successfully modulating α‐Syn synthesis in sporadic cases can be challenging. High intracellular levels of α‐Syn may increase its tendency to aggregate, together with other factors such as protein misfolding, limited proteolysis, mutations, and post‐transcriptional modifications such as phosphorylation and truncation . The processes of α‐Syn aggregation and fibrillation can be used as therapeutic targets for the development of drugs that act as conformational stabilizers and anti‐aggregation agents (e.g., small molecules, rifampicin).…”

AlphaLISA detection of alpha-synuclein in the cerebrospinal fluid and its potential application in Parkinson’s disease diagnosis

“…The accumulation and aggregation of α-syn is likely contributing to PD progression. The α-syn variant A53T (53 A→T) found in human patients has no effect on osmotic stress-induced phosphorylation, but increases oligomerization and exacerbates disease progression; suggesting a causal relationship between α-syn oligomerization and PD (Berrocal, Vasquez et al, 2014 ). Consistently, recent work suggested that monomeric α-syn level is likely reduced in cerebrospinal fluid (CSF) of the PD patients, while the oligomeric α-syn may increase (Aasly, Johansen et al, 2014 ).…”