Positive α-Synuclein staining of a Lewy body from a patient who had Parkinson's disease. Classically considered an unstructured soluble protein, unmutated α-synuclein forms a stably folded tetramer that resists aggregation. This observation, though reproduced and extended by several labs, is still a matter of debate in the field due to conflicting reports. Nevertheless,<unk>  aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. These disorders are known as<unk> ucleinopathies. In vitro models of<unk> ucleinopathies revealed that aggregation of<unk>  may lead to various cellular disorders including microtubule impairment,<unk> aptic and mitochondrial dysfunctions, oxidative stress as well as dysregulation of Calcium signaling, proteasomal and lysosomal pathway.<unk>  is the primary structural component of Lewy body fibrils. Occasionally, Lewy bodies contain tau protein; however,<unk>  and tau constitute two distinctive subsets of filaments in the same inclusion bodies.<unk>  pathology is also found in both sporadic and familial cases with Alzheimer's disease. The aggregation mechanism of<unk>  is uncertain. There is evidence of a structured intermediate rich in beta structure that can be the precursor of aggregation and, ultimately, Lewy bodies. A single molecule study in 2008 suggests<unk>  exists as a mix of unstructured,<unk> -helix, and beta-sheet-rich conformers in equilibrium. Mutations or buffer conditions known to improve aggregation strongly increase the population of the beta conformer, thus suggesting this could be a conformation related to pathogenic aggregation. One theory is that the majority of<unk>  aggregates are located in the presynapse as smaller deposits which causes<unk> aptic dysfunction. Among the strategies for treating<unk> ucleinopathies are compounds that inhibit aggregation of<unk> . It has been shown that the small molecule cuminaldehyde inhibits fibrillation of<unk> . The Epstein-Barr virus has been implicated in these disorders. In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for<unk> . Five point mutations have been identified thus far: A53T, A30P, E46K, H50Q, and G51D; however, in total, nineteen mutations in the SNCA gene have been associated with parkinsonism: A18T, A29S, A53E, A53V, E57A, V15A, T72M, L8I, V15D, M127I, P117S, M5T, G93A, E83Q, and A30G. It has been reported that some mutations influence the initiation and amplification steps of the aggregation process. Genomic duplication and triplication of the gene appear to be a rare cause of Parkinson's disease in other lineages, although more common than point mutations. Hence certain mutations of<unk>  may cause it to form amyloid-like fibrils that contribute to Parkinson's disease. Over-expression of human wild-type or A53T-mutant<unk>  in primates drives deposition of<unk>  in the ventral midbrain, degeneration of the dopaminergic system and impaired motor performance. Certain sections of the<unk>  protein may play a role in the tauopathies. A prion form of the protein<unk>  may be a causal agent for the disease multiple system atrophy. Events in α-synuclein toxicity.Self-replicating "prion-like" amyloid assemblies of<unk>  have been described that are invisible to the amyloid dye Thioflavin T and that can acutely spread in neurons in vitro and in vivo. Antibodies against<unk>  have replaced antibodies against ubiquitin as the gold standard for immunostaining of Lewy bodies. The central panel in the figure to the right shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify<unk> uclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport,<unk> aptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons.
Alpha-synuclein
Kamino bodies
Lewy body
Neurofibrillary tangle
Amyloid beta
Neurofilament light polypeptide
Hirano body
Wild-type transthyretin amyloid