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

作者：Wrasidlo Wolfgang; Tsigelny Igor F; Price Diana L; Dutta Garima; Rockenstein Edward; Schwarz Thomas C; Ledolter Karin; Bonhaus Douglas; Paulino Amy; Eleuteri Simona; Skjevik Age A; Kouznetsova Valentina L; Spencer Brian; Desplats Paula; Gonzalez Ruelas Tania; Trejo Morales Margarita; Overk Cassia R; Winter Stefan; Zhu Chunni; Chesselet Marie Francoise; Meier Dieter; Moessler Herbert; Konrat Robert; Masliah Eliezer^*

来源：Brain, 2016, 139(12): 3217-3236.

DOI：10.1093/brain/aww238

• alpha-synuclein
• Parkinson's disease
• experimental models
• cellular mechanisms
• synucleinopathy

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

• 出版日期2016-12