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
Affiliations
Aaron Held
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Michelle Adler
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Christine Marques
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Charles Jourdan Reyes
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
Amey S. Kavuturu
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Ana R.A.A. Quadros
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
I. Sandra Ndayambaje
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Erika Lara
iPSC Neurodegenerative Research Initiative, Center for Alzheimer’s and Related Dementias, National Institute on Aging, NIH, Bethesda, MD 20892, USA
Michael Ward
National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA
Clotilde Lagier-Tourenne
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
Brian J. Wainger
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; Corresponding author
Summary: 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.
