Theme 2: Molecular Basis of a-synuclein Aggregate Formation

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:

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.


For references see

2 Replies to “Theme 2: Molecular Basis of a-synuclein Aggregate Formation”

  1. Hi Lily – Nice work! I recently learned (reference below) that while synuclein is generally regarded as an intrinsically disordered protein (which you indicate above), it actually forms an ordered, N-terminal helix when it associates with membranes. I was wondering if you could comment on what this membrane association or dynamic nature of synuclein might indicate about its native function and/or the DLB pathology. Thanks!

    Zach Zimmerman (Biochem ’15)

    1. Hi Zach,
      Thank you for your question and for sharing this article! From the literature, it would seem that intrinsically disordered proteins tend to have roles in protein interaction and regulation of signalling pathways. The authors from this article propose that a-synuclein plays a role in mediating endo- and exocytosis of synaptic vesicles (1). Something that I recently learned is that researchers at UPenn are proposing that a-synuclein may be a neuron specific lectin. They found that a-synuclein binds specifically to complex, N-linked glycans. This would provide a possible explanation for the membrane association as well as the native function of a-synuclein, and would likely greatly aid in understanding the mechanism behind how a-synuclein is dysregulated in Lewy body dementia pathologies.


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