Alpha-Synuclein Aggregation

Alpha-synuclein (PARK1/SNCA) is the most common target of genetic mutation leading to Parkinson’s disease and the main component of Lewy bodies in both familial and sporadic PD, though other components, including neurofilaments and other cytoskeletal proteins, may be important for Lewy body formation. Unstructured alpha-synuclein is soluble and primarily found in neural tissue, where it likely functions in neurotransmission. However, alpha-synuclein can assume other structural conformations, becoming insoluble and forming protein aggregates. The insoluble forms are prone to oligomerization and fibril formation. Genomic rearrangement causing upregulation of alpha-synuclein expression through gene duplication events also promotes aggregation. However, it remains debatable which form of alpha-synuclein is the toxic species.

Common alpha-synuclein mutations (such as A53T and A30P) promote oligomerization (also called protofibrils). Because PD-associated mutations cause oligomer formation, it can be hypothesized that this is the toxic species, whereas only the A53T mutation promotes fibril formation (Yang et al., 2009; Cookson, 2005).  Aggregation of this species may be a protective mechanism, effectively sequestering potentially harmful proteins. Conformational change to a beta-sheet structure stabilizes the aggregates into fibrillous structures. This beta-sheet conformation is distinct from the native unstructured and lipid-bound forms.

In most cell culture models, toxicity is seen without the heavily aggregated species, possibly due to damage to vesicular membranes from the pore-like structure of the oligomeric species. This theory may also account for the selective death of dopaminergic neurons. Aggregate formation was shown to be protective in a Drosophila PD model and parkin was shown to enhance alpha-synuclein aggregation, resulting in decreased toxicity. However, further study is necessary to confirm the toxicity or protective function of aggregation.