Posted - September 2019 in Research Highlights
Potential drug target for SPG4 identified
New assays (tests) allowing rapid detection of 3 important HSP features (phenotypes) in neurons derived from stem cells have been developed.
A potential drug treatment, a liver X receptor (LXR) agonist that reversed the impairment in all three features has been identified.
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 just 24 hours after plating; axonal swellings, a hallmark of HSP pathology, were 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.
SOURCE: Sci Rep. 2019 Jul 3;9(1):9615. doi: 10.1038/s41598-019-45246-4. PMID: 31270336
Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons.
1 Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, 53127, Bonn, Germany.
2 LIFE & BRAIN GmbH, Cellomics Unit, 53127, Bonn, Germany.
3 Icahn School of Medicine, Mount Sinai, 10029, New York, United States.
4 German Centre for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany.
5 German Centre for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
6 Memorial Sloan Kettering Cancer Centre, 10065, New York, United States.
7 Department of Neurodegenerative Diseases, University of Tübingen, 72076, Tübingen, Germany.
8 Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, 53127, Bonn, Germany. [email protected]