Characterizing the inhibition of ?-synuclein oligomerization by a pharmacological chaperone that prevents prion formation by the protein PrP.

ABSTRACT: Aggregation of the disordered protein ?-synuclein into amyloid fibrils is a central feature of synucleinopathies, neurodegenerative disorders that include Parkinson's disease. Small, pre-fibrillar oligomers of misfolded ?-synuclein are thought to be the key toxic entities, and ?-synuclein misfolding can propagate in a prion-like way. We explored whether a compound with anti-prion activity that can bind to unfolded parts of the protein PrP, the cyclic tetrapyrrole Fe-TMPyP, was also active against ?-synuclein aggregation. Observing the initial stages of aggregation via fluorescence cross-correlation spectroscopy, we found that Fe-TMPyP inhibited small oligomer formation in a dose-dependent manner. Fe-TMPyP also inhibited the formation of mature amyloid fibrils in vitro, as detected by thioflavin T fluorescence. Isothermal titration calorimetry indicated Fe-TMPyP bound to monomeric ?-synuclein with a stoichiometry of 2, and two-dimensional heteronuclear single quantum coherence NMR spectra revealed significant interactions between Fe-TMPyP and the C-terminus of the protein. These results suggest commonalities among aggregation mechanisms for ?-synuclein and the prion protein may exist that can be exploited as therapeutic targets.

SUBMITTER: Dong C 

PROVIDER: S-EPMC6699102 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature