Inhibition of synucleinopathic seeding by rationally designed inhibitors

Abstract

Seeding, in the context of amyloid disease, is the sequential transfer of pathogenic protein aggregates from cell-to-cell within affected tissues. The structure of pathogenic seeds provides the molecular basis and enables rapid conversion of soluble protein into fibrils. To date, there are no inhibitors that specifically target seeding of Parkinson’s disease (PD)-associated α-synuclein (α-syn) fibrils, in part, due to lack of information of the structural properties of pathological seeds. Here we design small peptidic inhibitors based on the atomic structure of the core of α-syn fibrils. The inhibitors prevent α-syn aggregation in vitro and in cell culture models with binding affinities of 0.5 μM to α-syn fibril seeds. The inhibitors also show efficacy in preventing seeding by human patient-derived α-syn fibrils. Our results suggest that pathogenic seeds of α-syn contain steric zippers and suggest a therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.

Structures of α-synuclein filaments from multiple system atrophy

“…The finding that the structures of α-synuclein filaments from MSA differ from those of assembled recombinant proteins is consistent with the observation that rationally designed aggregation inhibitors of α-synuclein reduced aggregation by MSA and recombinant filament seeds to different extents (71). This finding is also reminiscent of similar results for tau filaments (4-9), even though marked differences exist between tau and α-synuclein.…”

Inhibitor and substrate cooperate to inhibit amyloid fibril elongation of α-synuclein

“…12 This is reminiscent of enzyme kinetics, and elongation can be treated as a two-step enzymatic reaction, in which bril-end and monomer serve as catalyst and substrate, respectively. [19][20][21] Proteins and peptides have been designed to specically inhibit the elongation of aS brils, [22][23][24][25] e.g., by aiming to dock complementary b-strands onto the open b-sheets at the brilends, to prevent the catalytic site from guiding the conformational conversion of further monomers. However, understanding how monomers and inhibitors get incorporated at bril-ends is still a subject of active research.…”

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

“…Another relevant mechanism that contributes to the propagation of neurodegeneration is the prion-like spread of α-syn aggregates. Indeed, experimental studies revealed that the injection of α-syn inclusions in animal’s brain promotes the formation of cellular inclusions at the injection site from where they can spread in other brain regions 11 . To date, the therapies available for the treatment of PD are addressed to reduce the motor symptoms and include the administration of drugs able to restore the level of dopamine.…”