Format

Send to

Choose Destination
Elife. 2020 Jan 2;9. pii: e46775. doi: 10.7554/eLife.46775. [Epub ahead of print]

Inhibition of synucleinopathic seeding by rationally designed inhibitors.

Author information

1
Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
2
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
3
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
4
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States.

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.

KEYWORDS:

biochemistry; chemical biology; human

PMID:
31895037
DOI:
10.7554/eLife.46775
Free full text

Conflict of interest statement

SS, SS, KM, SM, EG, LJ, CW, HV The other authors declare that no competing interests exist. MG Michel Goedert, Reviewing editor, eLife. DE David S Eisenberg, SAB member and equity holder in ADRx, Inc.

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd
Loading ...
Support Center