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000140787 1001_ $$0P:(DE-HGF)0$$aRehbach, Kristina$$b0
000140787 245__ $$aMultiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons.
000140787 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2019
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000140787 520__ $$aAxonal 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.
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000140787 542__ $$2Crossref$$i2019-07-03$$uhttps://creativecommons.org/licenses/by/4.0
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000140787 650_2 $$2MeSH$$aBiomarkers
000140787 650_2 $$2MeSH$$aCell Differentiation
000140787 650_2 $$2MeSH$$aCells, Cultured
000140787 650_2 $$2MeSH$$aDrug Discovery: methods
000140787 650_2 $$2MeSH$$aDrug Evaluation, Preclinical: methods
000140787 650_2 $$2MeSH$$aHaploinsufficiency
000140787 650_2 $$2MeSH$$aHumans
000140787 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: cytology
000140787 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: drug effects
000140787 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000140787 650_2 $$2MeSH$$aNeural Stem Cells: cytology
000140787 650_2 $$2MeSH$$aNeural Stem Cells: drug effects
000140787 650_2 $$2MeSH$$aNeural Stem Cells: metabolism
000140787 650_2 $$2MeSH$$aNeuronal Outgrowth
000140787 650_2 $$2MeSH$$aNeurons: drug effects
000140787 650_2 $$2MeSH$$aNeurons: metabolism
000140787 650_2 $$2MeSH$$aPhenotype
000140787 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: drug therapy
000140787 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: etiology
000140787 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: metabolism
000140787 650_2 $$2MeSH$$aSpastin: genetics
000140787 7001_ $$aKesavan, Jaideep$$b1
000140787 7001_ $$0P:(DE-2719)2810998$$aHauser, Stefan$$b2$$udzne
000140787 7001_ $$aRitzenhofen, Swetlana$$b3
000140787 7001_ $$0P:(DE-2719)2811320$$aJungverdorben, Johannes$$b4$$udzne
000140787 7001_ $$0P:(DE-2719)2812018$$aSchüle, Rebecca$$b5$$udzne
000140787 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b6$$udzne
000140787 7001_ $$0P:(DE-2719)9000249$$aPeitz, Michael$$b7$$udzne
000140787 7001_ $$0P:(DE-HGF)0$$aBrüstle, Oliver$$b8$$eCorresponding author
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