As is the case for any disease, knowing the difference between normal state and abnormal state is necessary in order to develop a successful treatment. In dementia with Lewy bodies (DLB), this means understanding how a-synuclein aggregates form. Despite two decades of research on a-synuclein, the question of how Lewy bodies form by protein aggregation is still under debate. Conventional belief holds that, under normal conditions, a-synuclein is found as a natively unfolded protein and exists as a monomer in the cytoplasm (7). However, recent studies indicate that it may exist as a tetramer and not as a monomer as previously believed.
Theory 1: Native a-synuclein exists as a monomer
Most research lists a-synuclein as a monomer. These studies propose that, in synucleinopathies, the a-synuclein undergoes structural/conformational change, causing the monomers to aggregate and become insoluble. Research study by Colom-Cadena et al, indicates that the changes in conformation are initiated when the protein binds or interacts with lipid surfaces, such as lipid membranes or phospholipid bilayers (10).This was discovered when a-synuclein monomers were exposed to a lipid surface and found to form dimers and oligomers. The pathogenesis of Lewy body diseases is associated with a number of a-synuclein conformers, including oligomers, protofibrils and fibrils (10). Fibrillar forms are mainly detected in Lewy bodies, which have been proposed as the cell’s attempt to convert the a-synuclein oligomers to fibrils (10).
Theory 2: Native a-synuclein exists as a tetramer
Figure 1. Image of ⍺-synuclein in its tetramer form. There is currently debate in the research community regarding the native form of a-synuclein; whether it exists as a monomer or multimer. Image source: http://www.pnas.org/content/108/43/17797
Recent studies dispute the claim that endogenous a-synuclein exists as a monomer and instead propose it exists as a tetramer. Researchers suggest that in the tetramer form, the protein is resistant to aggregation and it is disruptions to the structure, from post-translational modifications, that then render the protein more likely to aggregate (9).
Research supporting both theories propose that post-translational modification such as phosphorylation, ubiquitination and nitration have been implicated in the process of a-synuclein aggregation. The most common of these post-translational modifications is phosphorylation, which occurs primarily at serine residue S129 yet also to a lesser extend on a few other residues (7). In dementia with Lewy bodies (DLB), approximately 90% of insoluble a-synuclein in the brain is phosphorylated at S129, compared to 4% in soluble a-synuclein (7). Further research in which brains of DLB patients were compared to those of Alzheimer’s disease patients showed that phosphorylated a-synuclein was exclusively found in those with DLB (11). Altogether, these studies suggest a role for phosphorylation and post-translational modification in the formation of toxic a-synuclein aggregates in DLB in particular. Additionally, mutation present in the a-synuclein gene SNCA, is proposed to alter the ratio of monomer to tetramer in disease state (8).
a-synuclein oligomers act as prions
Many researchers believe that a-synuclein may act as a prion, meaning it becomes self-propagating. This phenomenon is well documented in multiple system atrophy (MSA), a synucleinopathy where a-synuclein aggregates form in oligodendrocytes. However, less research has been conducted on the potential prion properties of a-synuclein in neurons (12). Recent findings indicate that insoluble aggregates of a-synuclein fibrils have little seeding (the potential to propagate) ability in both phosphorylated and unphosphorylated states. On the other hand, a-synuclein oligomers both phosphorylated and unphosphorylated exhibit seeding activity. This research suggests that a-synuclein oligomers may be responsible for the prion-like behavior rather than mature fibrils (13). This is similar to what’s now believed to be the method of propagation of amyloid beta in Alzheimer’s Disease.
Although the main factor of the disease is age, there may be a genetic component involved. Researchers found that mutations in the gene encoding a-synuclein, SNCA, was a marker for familial PD (14). However, whether this plays a role in DLB remains to be seen.
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