3 Neuropore Therapies Inc.

San Diego, CA, United States

3 Neuropore Therapies Inc.

San Diego, CA, United States
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PubMed | University of Vienna, University of California at San Diego, 3 Neuropore Therapies Inc., University of California at Los Angeles and 8 EVER Neuropharma
Type: Journal Article | Journal: Brain : a journal of neurology | Year: 2016

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

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