Dopamine and L‐dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease

Abstract

Protein deposition diseases involve the aggregation of normally soluble proteins, leading to both fibrillar and amorphous deposits. The aggregation of alpha-synuclein is associated with Parkinson's disease, and the aggregation of the Abeta peptide is associated with Alzheimer's disease. Here we show that L-dopa, dopamine, and other catecholamines dissolve fibrils of alpha-synuclein and Abeta peptide generated in vitro. The catecholamines also inhibited the fibrillation of these proteins. In addition, intraneuronal alpha-synuclein deposits formed in a mouse model were dissolved by incubation of tissue slices with L-dopa. These catecholamines are susceptible to oxidative breakdown, and we show that oxidation products are more effective than the parent compounds in inhibition. The ability to dissolve fibrils provides a new approach for studying mechanisms and consequences (e.g., the relationship between fibril formation and neurodegeneration) of protein aggregation. It is also likely to help in the development of strategies for the prevention and treatment of protein deposition diseases.

Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations

“…First, using mass spectrometry we and others (46) were unable to detect significant amounts of ␣-syn dopamine adducts, which is consistent with findings that dopamine can inhibit ␣-syn filament formation at sub-stoichiometric concentrations (37). Second, under the conditions used here that inhibit ␣-syn fila- ment formation, only a minute amount of ␣-syn was covalently modified by dopamine (Ͻ0.1%), as demonstrated by using [ 3 H] dopamine in radiolabeling studies (data not shown).…”

“…It is hypothesized that dopaminergic neurons may be selectively vulnerable in PD because of their increased exposure to oxidation stress as a result of dopamine biochemistry. However, our data here suggest that intermediates in dopamine oxidation may prevent the formation of ␣-syn filaments, although other catecholamines might have similar effects (37,46). Nevertheless, it remains to be determined if spherical oligomers generated because of dopamine oxidation have any toxic effects.…”

“…It also is difficult to assess how many oxidized dopamine intermediates exist in cells at steady state, because it is likely that these compounds readily convert to neuromelanin. It is also interesting to speculate that a reduction in dopamine levels may occur early in PD and result in an increased propensity for WT ␣-syn to form fibrillar inclusions, but this may partially be countered by L-dopa, which has a similar effect on ␣-syn filament formation as dopamine (37,46). Although LB-like inclusions with mature ␣-syn fibrils developed in multiple brain regions in animal models of synucleinopathies (47,48), dopaminergic neurons such as those in substantia nigra are remarkably spared and devoid of LB-like inclusions, suggesting that normal dopamine levels may prevent ␣-syn fibrillogenesis in vivo.…”

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

“…The antioxidant compounds with hydroxyphenyl rings are suggested to bind specifically to Aß and/or fAß, inhibit fAß formation and/or destabilize preformed fAß (Ono et al, 2002b;2004a;2004b;Li et al, 2004). On the other hand, the NSAIDs examined in this study have no hydroxyphenyl rings (Fig.…”

Protein self‐modification by heme‐generated reactive species

“…The DAQ modification of target proteins can apparently induce changes in their structures and properties, aggregation, precipitation, and, in some instances, promote cell death. In fact, DAQ-protein adduct formation has been shown to stabilize protofibrillar aggregates of a-synuclein, thus preventing the formation of insoluble amyloidogenic fibrils (103,104), and to induce the formation of insoluble, SDS-stable, and large aggregates of parkin (45).…”