2. Academic Validation
  3. iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons

iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons

  • Cell Rep. 2023 Aug 30;42(9):113046. doi: 10.1016/j.celrep.2023.113046.
Aaron Held 1,  Michelle Adler 1,  Christine Marques 1,  Charles Jourdan Reyes 2,  Amey S Kavuturu 1,  Ana R A A Quadros 1,  I Sandra Ndayambaje 1,  Erika Lara 3,  Michael Ward 4,  Clotilde Lagier-Tourenne 5,  Brian J Wainger 6
Affiliations

Affiliations

  • 1 Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 2 Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-Linked Dystonia-Parkinsonism, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • 3 iPSC Neurodegenerative Research Initiative, Center for Alzheimer's and Related Dementias, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
  • 4 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
  • 5 Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard University and MIT, Cambridge MA 02142, USA.
  • 6 Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard University and MIT, Cambridge MA 02142, USA; Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston MA 02114, USA; Harvard Stem Cell Institute, Cambridge MA 02138, USA. Electronic address: brian.wainger@mgh.harvard.edu.
PMID: 37651231 DOI: 10.1016/j.celrep.2023.113046
Abstract

Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not Other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not Other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology.

Keywords

ALS; CP: Neuroscience; CP: Stem cell research; TDP-43; cell-type specificity; disease modeling; nonsense-mediated decay; splicing.

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