Journal Article

DZNE-2020-07109

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons.

Rehbach, K. ; Kesavan, J. ; Hauser, S.DZNE* ; Ritzenhofen, S. ; Jungverdorben, J.DZNE* ; Schüle, R.DZNE* ; Schöls, L.DZNE* ; Peitz, M.DZNE* ; Brüstle, O. (Corresponding author)

2019
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-019-45246-4

Abstract: 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.

Keyword(s): Biomarkers (MeSH) ; Cell Differentiation (MeSH) ; Cells, Cultured (MeSH) ; Drug Discovery: methods (MeSH) ; Drug Evaluation, Preclinical: methods (MeSH) ; Haploinsufficiency (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; Induced Pluripotent Stem Cells: drug effects (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Neural Stem Cells: cytology (MeSH) ; Neural Stem Cells: drug effects (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; Neuronal Outgrowth (MeSH) ; Neurons: drug effects (MeSH) ; Neurons: metabolism (MeSH) ; Phenotype (MeSH) ; Spastic Paraplegia, Hereditary: drug therapy (MeSH) ; Spastic Paraplegia, Hereditary: etiology (MeSH) ; Spastic Paraplegia, Hereditary: metabolism (MeSH) ; Spastin: genetics (MeSH)

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Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)
2. Cell Programming Unit (Cell Programming Unit)
3. Functional Neurogeriatrics (AG Maetzler)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2019

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; IF < 5 ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record

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