Home > Publications Database > Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons. > print

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024 7 _ |a 10.1038/s41598-019-45246-4
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024 7 _ |a pmc:PMC6610147
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037 _ _ |a DZNE-2020-07109
041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Rehbach, Kristina
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245 _ _ |a Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons.
260 _ _ |a [London]
|c 2019
|b Macmillan Publishers Limited, part of Springer Nature
264 _ 1 |3 online
|2 Crossref
|b Springer Science and Business Media LLC
|c 2019-07-03
264 _ 1 |3 print
|2 Crossref
|b Springer Science and Business Media LLC
|c 2019-12-01
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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520 _ _ |a Axonal degeneration is a key pathology of neurodegenerative diseases, including hereditary spastic paraplegia (HSP), a disorder characterized by spasticity in the lower limbs. Treatments for HSP and other neurodegenerative diseases are mainly symptomatic. While iPSC-derived neurons are valuable for drug discovery and target identification, these applications require robust differentiation paradigms and rapid phenotypic read-outs ranging between hours and a few days. Using spastic paraplegia type 4 (SPG4, the most frequent HSP subtype) as an exemplar, we here present three rapid phenotypic assays for uncovering neuronal process pathologies in iPSC-derived glutamatergic cortical neurons. Specifically, these assays detected a 51% reduction in neurite outgrowth and a 60% increase in growth cone area already 24 hours after plating; axonal swellings, a hallmark of HSP pathology, was discernible after only 5 days. Remarkably, the identified phenotypes were neuron subtype-specific and not detectable in SPG4-derived GABAergic forebrain neurons. We transferred all three phenotypic assays to a 96-well setup, applied small molecules and found that a liver X receptor (LXR) agonist rescued all three phenotypes in HSP neurons, providing a potential drug target for HSP treatment. We expect this multiparametric and rapid phenotyping approach to accelerate development of therapeutic compounds for HSP and other neurodegenerative diseases.
536 _ _ |a 345 - Population Studies and Genetics (POF3-345)
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542 _ _ |i 2019-07-03
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|u https://creativecommons.org/licenses/by/4.0
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 2 |a Biomarkers
|2 MeSH
650 _ 2 |a Cell Differentiation
|2 MeSH
650 _ 2 |a Cells, Cultured
|2 MeSH
650 _ 2 |a Drug Discovery: methods
|2 MeSH
650 _ 2 |a Drug Evaluation, Preclinical: methods
|2 MeSH
650 _ 2 |a Haploinsufficiency
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: cytology
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: drug effects
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Neural Stem Cells: cytology
|2 MeSH
650 _ 2 |a Neural Stem Cells: drug effects
|2 MeSH
650 _ 2 |a Neural Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Neuronal Outgrowth
|2 MeSH
650 _ 2 |a Neurons: drug effects
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Phenotype
|2 MeSH
650 _ 2 |a Spastic Paraplegia, Hereditary: drug therapy
|2 MeSH
650 _ 2 |a Spastic Paraplegia, Hereditary: etiology
|2 MeSH
650 _ 2 |a Spastic Paraplegia, Hereditary: metabolism
|2 MeSH
650 _ 2 |a Spastin: genetics
|2 MeSH
700 1 _ |a Kesavan, Jaideep
|b 1
700 1 _ |a Hauser, Stefan
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700 1 _ |a Ritzenhofen, Swetlana
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700 1 _ |a Jungverdorben, Johannes
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700 1 _ |a Schüle, Rebecca
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700 1 _ |a Schöls, Ludger
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700 1 _ |a Peitz, Michael
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700 1 _ |a Brüstle, Oliver
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773 1 8 |a 10.1038/s41598-019-45246-4
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773 _ _ |a 10.1038/s41598-019-45246-4
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856 4 _ |y OpenAccess
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856 7 _ |2 Pubmed Central
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