ArticleScientific reports2019
Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 51 citations in OpenAlex.
- Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology.Cell reports · 2026Article
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- Current Applications of Human Pluripotent Stem Cells in Neuroscience Research and Cell Transplantation Therapy for Neurological Disorders.Stem cell reviews and reports · 2025Review
- Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Dominant negative effect as a novel mechanism of SPAST gene mutation in a large family with hereditary spastic paraplegia.Genes & diseases · 2024Article
- A novel truncated variant in SPAST results in spastin accumulation and defects in microtubule dynamics.BMC medical genomics · 2023Article
- Using Human-Induced Pluripotent Stem Cell Derived Neurons on Microelectrode Arrays to Model Neurological Disease: A Review.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Review
- Recent Advances in High-Content Imaging and Analysis in iPSC-Based Modelling of Neurodegenerative Diseases.International journal of molecular sciences · 2023Review
- Novel mutation ofWorld journal of clinical cases · 2023Article
- Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients.Orphanet journal of rare diseases · 2023Article
- Pharmacological rescue of mitochondrial and neuronal defects inFrontiers in neuroscience · 2023Article
- The interconnection of endoplasmic reticulum and microtubule and its implication in Hereditary Spastic Paraplegia.Computational and structural biotechnology journal · 2023Review
- Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia.Brain : a journal of neurology · 2022Article
- A specific, non-immune system-related isoform of the human inducible nitric oxide synthase is expressed during differentiation of human stem cells into various cell types.Cell communication and signaling : CCS · 2022Article
- Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons.Molecular therapy. Nucleic acids · 2022Article
- Exploring Motor Neuron Diseases Using iPSC Platforms.Stem cells (Dayton, Ohio) · 2022Article
- Monitoring Axonal Degeneration in Human Pluripotent Stem Cell Models of Hereditary Spastic Paraplegias.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Molecular and cellular mechanisms of spastin in neural development and disease (Review).International journal of molecular medicine · 2021Review
- Review
- Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery.Brain sciences · 2021Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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