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A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease

Authors :
Eliezer Masliah
Amy Paulino
Karin Ledolter
Paula Desplats
Wolfgang Wrasidlo
Igor F. Tsigelny
Dieter Meier
Åge A. Skjevik
Margarita Trejo-Morales
Brian Spencer
Robert Konrat
Chunni Zhu
Garima Dutta
Simona Eleuteri
Marie-Françoise Chesselet
Tania Gonzalez-Ruelas
Cassia R. Overk
Edward Rockenstein
Thomas C. Schwarz
Diana L. Price
Douglas W. Bonhaus
Valentina L. Kouznetsova
Herbert Moessler
Stefan Winter
Source :
Brain : a journal of neurology, vol 139, iss Pt 12
Publication Year :
2016
Publisher :
eScholarship, University of California, 2016.

Abstract

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.

Details

Database :
OpenAIRE
Journal :
Brain : a journal of neurology, vol 139, iss Pt 12
Accession number :
edsair.doi.dedup.....94e17d784387b62c9ca849ff394fe12f