Aggregation of alph-synuclein in Lewy bodies of sporadic Parkinsons disease and dementia with Lewy bodies

Aggregation of alph-synuclein in Lewy bodies of sporadic Parkinsons disease and dementia with Lewy bodies. (±)-Ibipinabant at protecting cells against the cytotoxicity of -synuclein. These strategies may lead to the development of therapeutic agents that could prove useful in combating this disease. as well as to demonstrate neurotoxicity in rat PC12 cells [31]. As with other amyloid fibril forming polypeptides, the kinetics of amyloidogenesis implies a nucleation-dependent polymerization with three phases: a lag phase, a growth phase, and a final plateau in fibril formation as measured by thiolflavin T (ThT) fluorescence experiments [32]. Insights from Mutational Studies of -syn One characteristic of early onset PD has been the duplication or triplication of the gene locus for -synuclein resulting in overproduction of the protein [33, 34]. This likely reflects the concentration dependence of -syn amyloidogenesis [4]. Early onset PD has also been linked to a number of single site mutations of the -syn (±)-Ibipinabant sequence. Some of the common mutations in familial Parkinsonism identified so far are A53T, A30P, E46K and H50Q mutations. These mutations act in different ways to enhance the toxicity of -syn. The A53T, E46K and H50Q mutations have been shown to increase the rate of formation of soluble oligomers [35-37]. On the other hand, the A30P mutation does not increase the rate of formation of oligomers but it does delay the transition from oligomers to insoluble fibrils; this has been proposed to be the basis for cytotoxicity of this mutation [38]. An in depth study into the structure and dynamics of the A53T and A30P mutants provided insights into the effect of these mutations on membrane binding by -syn. The results indicate that the A53T mutation results in no significant perturbation of the structure of -syn, but the A30P mutations effect can be observed up to 30 residues on either side of the mutation. There is in fact evidence that the helical character of -syn in the presence of micelles is slightly increased with the presence of the A53T mutation. However, despite the A30P mutations effect on -syn structure, these do not result in a significant change in micelle binding. The presence of the mutation does rearrange the two helices formed in the presence of micelles, by shifting the helix break to the proline site, the N-terminal helix is able to reduce curvature strain and the boundary of the C-terminal helix is shifted to residue 92. This change in -syn conformational preference results in a slight change in the micelle shape, but no net decrease in binding is observed [39]. A recent study by Pasanen A78T and V63P, led to decreased rates of amyloidogenesis. In particular, proline mutations in this region led to a dramatic increase in lag phase [42]. A Rabbit Polyclonal to SRY more (±)-Ibipinabant specific study that probed the role of residues 71 to 82 within the NAC region showed that the mutation of a single residue (A76) to either a positively charged residue or a negatively charged residue resulted in significant increases to the rate of amyloidogenesis [43]. The study also showed that the NAC region formed the core of -syn fibrils thus confirming its pivotal (±)-Ibipinabant role in amyloidogenesis. Role of the C-terminus in Amyloidogenesis The C-terminal tail of -syn may be involved in some interactions that modulate amyloidogenesis. Long range interactions between aromatic residues in the tail and residues within the NAC region of -syn have been detected [44, 45] and these transient interactions may inhibit the formation of fibrils. However, a study that mutated all the tyrosine residues in -syn to alanine showed that amyloidogenesis was completely inhibited when all 3 of the tyrosine residues in the C-terminus were mutated simultaneously, or if the single tyrosine residue in the N-terminus, Y39 was mutated. Aggregation inhibition was also complete (±)-Ibipinabant when only Y133 in the C-terminus was.