Dataset Information

Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons.

ABSTRACT: Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3?/?Cat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3? inhibitor, tideglusib, to rescue neurodegeneration associated characteristics in an induced pluripotent stem cells (iPSCs) derived neuronal model from SPG11 patients and matched healthy controls as well as a CRISPR-Cas9 mediated SPG11 knock-out line and respective control. SPG11-iPSC derived cortical neurons, as well as the genome edited neurons exhibited shorter and less complex neurites than controls. Administration of tideglusib to these lines led to the rescue of neuritic impairments. Moreover, the treatment restored increased cell death and ameliorated the membranous inclusions in iPSC derived SPG11 neurons. Our results provide a first evidence for the rescue of neurite pathology in SPG11-HSP by tideglusib. The current lack of disease-modifying treatments for SPG11 and related types of complicated HSP renders tideglusib a candidate compound for future clinical application.

SUBMITTER: Pozner T

PROVIDER: S-EPMC6291617 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons.

Pozner Tatyana T Schray Annika A Regensburger Martin M Lie Dieter Chichung DC Schlötzer-Schrehardt Ursula U Winkler Jürgen J Turan Soeren S Winner Beate B

Frontiers in neuroscience 20181206

Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3β/βCat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3β inhibitor, tideglusib, to rescue neurodegeneration associated characteristics in an induced pluripotent stem cells (iPSCs) derived neuronal model from SPG11 patients and matched healthy controls as well as a CRISPR-Cas9 media ...[more]

PMID: 30574063

Similar Datasets

Project description:Due to the increasing number of drugs and untested environmental compounds introduced into commercial use, there is recognition for a need to develop reliable and efficient screening methods to identify compounds that may adversely impact the nervous system. One process that has been implicated in neurodevelopment is neurite outgrowth; the disruption of which can result in adverse outcomes that persist later in life. Here, we developed a green fluorescent protein (GFP) labeled neurite outgrowth assay in a high-content, high-throughput format using induced pluripotent stem cell (iPSC) derived human spinal motor neurons and cortical glutamatergic neurons. The assay was optimized for use in a 1536-well plate format. Then, we used this assay to screen a set of 84 unique compounds that have previously been screened in other neurite outgrowth assays. This library consists of known developmental neurotoxicants, environmental compounds with unknown toxicity, and negative controls. Neurons were cultured for 40 h and then treated with compounds at 11 concentrations ranging from 1.56 nM to 92 μM for 24 and 48 h. Effects of compounds on neurite outgrowth were evaluated by quantifying total neurite length, number of segments, and maximum neurite length per cell. Among the 84 tested compounds, neurite outgrowth in cortical neurons and motor neurons were selectively inhibited by 36 and 31 compounds, respectively. Colchicine, rotenone, and methyl mercuric (II) chloride inhibited neurite outgrowth in both cortical and motor neurons. It is interesting to note that some compounds like parathion and bisphenol AF had inhibitory effects on neurite outgrowth specifically in the cortical neurons, while other compounds, such as 2,2',4,4'-tetrabromodiphenyl ether and caffeine, inhibited neurite outgrowth in motor neurons. The data gathered from these studies show that GFP-labeled iPSC-derived human neurons are a promising tool for identifying and prioritizing compounds with developmental neurotoxicity potential for further hazard characterization.

Dataset Information

Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons.

Publications

Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets