Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Hum Mol Genet ; 28(6): 961-971, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30476097

ABSTRACT

Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For the delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients' iPSC and controls. We reveal that an increased rate of asymmetric divisions of NPCs leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including the Food and Drug Administration-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology.


Subject(s)
Cerebral Cortex/embryology , Cerebral Cortex/metabolism , Neurogenesis/genetics , Proteins/genetics , Alleles , Biomarkers , Cerebral Cortex/physiopathology , Cognition Disorders/genetics , Cognition Disorders/physiopathology , Disease Susceptibility , Fluorescent Antibody Technique , Genotype , Glycogen Synthase Kinase 3/metabolism , Humans , Mutation , Organoids , Phenotype , beta Catenin
2.
Front Neurosci ; 12: 914, 2018.
Article in English | MEDLINE | ID: mdl-30574063

ABSTRACT

Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3ß/ßCat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3ß 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.

SELECTION OF CITATIONS
SEARCH DETAIL
...