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

Aaron Held; Michelle Adler; Christine Marques; Charles Jourdan Reyes; Amey S Kavuturu; Ana R A A Quadros; I Sandra Ndayambaje; Erika Lara; Michael Ward; Clotilde Lagier-Tourenne; Brian J Wainger

doi:10.1016/j.celrep.2023.113046

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

Cell Rep. 2023 Sep 26;42(9):113046. doi: 10.1016/j.celrep.2023.113046. Epub 2023 Aug 30.

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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amyotrophic Lateral Sclerosis* / pathology
DNA-Binding Proteins / metabolism
Gene Expression
Humans
Induced Pluripotent Stem Cells* / metabolism
Motor Neurons / metabolism

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

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