This type of research is really important... it shows that a drug can reduce the formation and accumulation of alpha-synuclein (the key protein that underlies PD) and also reduce evidence of damage caused by it. The authors then show its activity in mouse models that have excessive alpha-synuclein... It is important to learn what other effects these compounds have before considering them to be potentially trialled as treatment, but very encouraging to know that things affect the burden of synuclein!!
Brain. 2016 Sep 27. pii: aww238. [Epub ahead of print]
Wrasidlo W, Tsigelny IF, Price DL, Dutta G, Rockenstein E, Schwarz TC, Ledolter K, Bonhaus D, Paulino A, Eleuteri S, Skjevik ÅA, Kouznetsova VL, Spencer B, Desplats P, Gonzalez-Ruelas T, Trejo-Morales M, Overk CR, Winter S, Zhu C, Chesselet MF, Meier D, Moessler H, Konrat R, Masliah E.
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.
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