March 2018
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16 Reads
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Publications (2)
![Figure 2. Niclosamide analogue AM85 activatesP INK1 in HeLa cells and uncouples mitochondria. A) Chemical structures of niclosamidea nalogues AM85, AM86, and AM87. B) WT HeLa cells transfected with Parkinw ere stimulated with either ac ombination of A/O for 3hor 10 mm niclosamide (Niclo), AM85,AM86, AM87, for 40 min. C) WT and PINK1 knockout (PINK1 KO) HeLa cells transfected with Parkin were stimulated with A/O for 3hor with different concentrations( 0.2, 0.8, 2, 8, 20 mm)ofA M85 for 40 min. ParkinS er65p hosphorylation (pS65Parkin), Parkin, full-length OPA1 (F/L), cleaved OPA1, ubiquitylated CISD1 (CISD1-Ub), and CISD1 were detected by immunoblotting.Glyceraldehyde 3-phosphatedehydrogenase (GAPDH) was used as aloading control. D) Histograms of CMXRos relative fluorescenceintensity [arbitrary units] for HeLa cells treatedo ns ite for 3hwith A/O (green) or for 1hwith niclosamide(Niclo, red) and AM85 (blue). Data are normalized to the vehicle DMSO set at 1( black). E) Quantification of CMXRos relative fluorescence intensity [a.u.] for HeLacells subjected to drug wash out, after treatment with A/O (green), niclosamide (Niclo, red), AM85 (blue). Data are normalized to the vehicle DMSO set at 1( black). Barsrepresent the average ratio AE SEMo ft hree independent experiments. ** p < 0.01, one-way analysis of variance (ANOVA) followed by Bonferroni post-test correction.](https://www.researchgate.net/publication/321727239/figure/fig2/AS:619513674493952@1524714978659/Niclosamide-analogue-AM85-activatesP-INK1-in-HeLa-cells-and-uncouples-mitochondria-A_Q320.jpg)
December 2017
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598 Reads
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52 Citations
Mutations in PINK1, which impair its catalytic kinase activity, are causal for autosomal recessive early onset Parkinson's disease (PD). Various studies have indicated that the activation of PINK1 could be a useful strategy in treating neurodegenerative diseases such as PD. Herein, we show that the anthelmintic drug niclosamide and its analogues are capable of activating PINK1 in cells via reversible impairment of the mitochondrial membrane potential. Using these compounds, we demonstrate for the first time that the PINK1 pathway is active and detectable in primary neurons. Our findings suggest that niclosamide and its analogues are robust compounds to study the PINK1 pathway and may hold promise as a therapeutic strategy in Parkinson's and related disorders.
Citations (1)
... Notably, most research relies on neuronal cultures at early maturation stages or exogenously expressed Parkin 85,93-95 . As previ ous studies have shown, Parkin expression increases with neuronal maturation 96 , correlating with synaptic maturation in vitro 43,96,97 and its localization at both presynaptic 98,99 and postsynaptic terminals in vivo 100,101 . Additionally, neurons undergo extensive mitochondrial metabolic reprogramming during differentiation to reach the final stage of oxidative phosphorylation 102,103 and neuronal maturation, for example, highly structured morphology, electrical excitability and functional synapses 103 . ...
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December 2017