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@ARTICLE{Rehbach:140787,
      author       = {Rehbach, Kristina and Kesavan, Jaideep and Hauser, Stefan
                      and Ritzenhofen, Swetlana and Jungverdorben, Johannes and
                      Schüle, Rebecca and Schöls, Ludger and Peitz, Michael and
                      Brüstle, Oliver},
      title        = {{M}ultiparametric rapid screening of neuronal process
                      pathology for drug target identification in {HSP}
                      patient-specific neurons.},
      journal      = {Scientific reports},
      volume       = {9},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {DZNE-2020-07109},
      pages        = {9615},
      year         = {2019},
      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.},
      keywords     = {Biomarkers / Cell Differentiation / Cells, Cultured / Drug
                      Discovery: methods / Drug Evaluation, Preclinical: methods /
                      Haploinsufficiency / Humans / Induced Pluripotent Stem
                      Cells: cytology / Induced Pluripotent Stem Cells: drug
                      effects / Induced Pluripotent Stem Cells: metabolism /
                      Neural Stem Cells: cytology / Neural Stem Cells: drug
                      effects / Neural Stem Cells: metabolism / Neuronal Outgrowth
                      / Neurons: drug effects / Neurons: metabolism / Phenotype /
                      Spastic Paraplegia, Hereditary: drug therapy / Spastic
                      Paraplegia, Hereditary: etiology / Spastic Paraplegia,
                      Hereditary: metabolism / Spastin: genetics},
      cin          = {AG Schöls / Cell Programming Unit / AG Maetzler},
      ddc          = {600},
      cid          = {I:(DE-2719)5000005 / I:(DE-2719)1013013 /
                      I:(DE-2719)5000024},
      pnm          = {345 - Population Studies and Genetics (POF3-345) / 344 -
                      Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-345 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31270336},
      pmc          = {pmc:PMC6610147},
      doi          = {10.1038/s41598-019-45246-4},
      url          = {https://pub.dzne.de/record/140787},
}