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

ABSTRACT: Abnormal accumulation and propagation of the neuronal protein ?-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 ?-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 Parkinson's disease and other synucleinopathies.

SUBMITTER: Wrasidlo W

PROVIDER: S-EPMC5840882 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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

Wrasidlo Wolfgang W Tsigelny Igor F IF Price Diana L DL Dutta Garima G Rockenstein Edward E Schwarz Thomas C TC Ledolter Karin K Bonhaus Douglas D Paulino Amy A Eleuteri Simona S Skjevik Åge A ÅA Kouznetsova Valentina L VL Spencer Brian B Desplats Paula P Gonzalez-Ruelas Tania T Trejo-Morales Margarita M Overk Cassia R CR Winter Stefan S Zhu Chunni C Chesselet Marie-Francoise MF Meier Dieter D Moessler Herbert H Konrat Robert R Masliah Eliezer E

Brain : a journal of neurology 20160927 Pt 12

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 ...[more]

PMID: 27679481

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Project description:BACKGROUND:Commonly used neuroimaging biomarkers in Parkinson's disease (PD) are useful for diagnosis but poor at predicting outcomes. We explored whether an atrophy pattern from whole-brain structural MRI, measured in the drug-naïve early stage, could predict PD prognosis. METHODS:362 de novo PD patients with T1-weighted MRI (n = 222 for the main analysis, 140 for the validation analysis) were recruited from the Parkinson's Progression Markers Initiative (PPMI). We investigated a previously identified PD-specific network atrophy pattern as a potential biomarker of disease severity and prognosis. Progression trajectories of motor function (MDS-UPDRS-part III), cognition (Montreal Cognitive Assessment (MoCA)), and a global composite outcome measure were compared between atrophy tertiles using mixed effect models. The prognostic value of the MRI atrophy measure was compared with 123I ioflupane single photon emission computed tomography, the postural-instability-gait-disturbance score, and cerebrospinal fluid markers. FINDINGS:After 4.5 years follow-up, PD-specific atrophy network score at baseline significantly predicted change in UPDRS-part III (r = -0.197, p = .003), MoCA (r = 0.253, p = .0002) and global composite outcome (r = -0.249, p = .0002). Compared with the 3rd tertile (i.e. least atrophy), the tertile with the highest baseline atrophy (i.e. the 1st tertile) had a 3-point annual faster progression in UPDRS-part III (p = .012), faster worsening of posture-instability gait scores (+0.21 further annual increase, p < .0001), faster decline in MoCA (-0.74 further annual decline in MoCA, p = .0372) and a + 0.38 (p = .0029) faster annual increase in the global composite z-score. All findings were replicated in a validation analysis using 1.5T MRI. Receiver operating characteristic analysis confirmed the superiority of the MRI biomarker, although it had modest AUC values (0.63). By comparison, the other biomarkers were limited in their ability to predict prognosis either in the main or validation analysis. INTERPRETATION:A PD-specific network atrophy pattern predicts progression of motor, cognitive, and global outcome in PD, and is a better predictor of prognosis than any of the other tested biomarkers. Therefore, it has potential as a prognostic biomarker for clinical trials of early PD.

Dataset Information

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

Publications

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

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