Abstract
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 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.
Highlights
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of motor neuron disorders
The neuronal differentiation yields in cortical neurons expressing a majority of Tuj-1 positive cells with astrocytes comprising less than 10% of the cellular population
Our findings indicate a beneficial effect of tideglusib on both cellular morphology and survival of SPG11-induced pluripotent stem cells (iPSCs)-derived neurons
Summary
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of motor neuron disorders. HSP manifests with progressive lower limb spasticity and weakness due to axonopathy of corticospinal motor neurons and ascending dorsal columns. More than 70 distinct genetic loci (Spastic Paraplegia Gene SPG1-SPG79) and mutations in more than 50 genes have been identified in HSP patients (Lo Giudice et al, 2014; Novarino et al, 2014). Mutations in SPG11 are the most common genetic cause of AR complicated HSP. Apart from spastic paraparesis, SPG11 patients present with additional phenotypes that in the majority of cases include cognitive impairment, thin corpus callosum (TCC), neuropathy, and amyotrophy (Lo Giudice et al, 2014). Mutations in SPG11 encoding spatacsin, were found in other motor neuron diseases such as AR juvenile-onset amyotrophic lateral sclerosis (ALS5) and Rescue of Neurite Pathology in SPG11
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