Frontiers in Cellular Neuroscience (Jun 2023)
Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features
- Ileana Lorenzini,
- Eric Alsop,
- Jennifer Levy,
- Lauren M. Gittings,
- Deepti Lall,
- Benjamin E. Rabichow,
- Stephen Moore,
- Stephen Moore,
- Ryan Pevey,
- Ryan Pevey,
- Lynette M. Bustos,
- Lynette M. Bustos,
- Camelia Burciu,
- Divya Bhatia,
- Mo Singer,
- Justin Saul,
- Amanda McQuade,
- Amanda McQuade,
- Amanda McQuade,
- Makis Tzioras,
- Makis Tzioras,
- Thomas A. Mota,
- Amber Logemann,
- Jamie Rose,
- Jamie Rose,
- Sandra Almeida,
- Fen-Biao Gao,
- Michael Marks,
- Christopher J. Donnelly,
- Elizabeth Hutchins,
- Shu-Ting Hung,
- Justin Ichida,
- Robert Bowser,
- Tara Spires-Jones,
- Tara Spires-Jones,
- Mathew Blurton-Jones,
- Mathew Blurton-Jones,
- Mathew Blurton-Jones,
- Tania F. Gendron,
- Tania F. Gendron,
- Robert H. Baloh,
- Robert H. Baloh,
- Kendall Van Keuren-Jensen,
- Rita Sattler
Affiliations
- Ileana Lorenzini
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Eric Alsop
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
- Jennifer Levy
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Lauren M. Gittings
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Deepti Lall
- Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Regenerative Medicine Institute, Los Angeles, CA, United States
- Benjamin E. Rabichow
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Stephen Moore
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Stephen Moore
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
- Ryan Pevey
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Ryan Pevey
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
- Lynette M. Bustos
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Lynette M. Bustos
- School of Life Sciences, Arizona State University, Tempe, AZ, United States
- Camelia Burciu
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Divya Bhatia
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Mo Singer
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Justin Saul
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Amanda McQuade
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Amanda McQuade
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, United States
- Amanda McQuade
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
- Makis Tzioras
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Makis Tzioras
- Centre for Brain Discovery Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Thomas A. Mota
- Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Regenerative Medicine Institute, Los Angeles, CA, United States
- Amber Logemann
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
- Jamie Rose
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Jamie Rose
- Centre for Brain Discovery Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Sandra Almeida
- 0Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States
- Fen-Biao Gao
- 0Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States
- Michael Marks
- 1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Christopher J. Donnelly
- 1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Elizabeth Hutchins
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
- Shu-Ting Hung
- 2Department of Stem Cell Biology Regenerative Medicine, USC Keck School of Medicine, Los Angeles, CA, United States
- Justin Ichida
- 2Department of Stem Cell Biology Regenerative Medicine, USC Keck School of Medicine, Los Angeles, CA, United States
- Robert Bowser
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- Tara Spires-Jones
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Tara Spires-Jones
- Centre for Brain Discovery Sciences, The University of Edinburgh, Edinburgh, United Kingdom
- Mathew Blurton-Jones
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States
- Mathew Blurton-Jones
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, United States
- Mathew Blurton-Jones
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
- Tania F. Gendron
- 3Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Tania F. Gendron
- 4Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, United States
- Robert H. Baloh
- Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Regenerative Medicine Institute, Los Angeles, CA, United States
- Robert H. Baloh
- 5Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Kendall Van Keuren-Jensen
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
- Rita Sattler
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
- DOI
- https://doi.org/10.3389/fncel.2023.1179796
- Journal volume & issue
-
Vol. 17
Abstract
While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.
Keywords
