Moderate intrinsic phenotypic alterations in ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features

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.
Ryan Pevey, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States.
Lynette M. Bustos, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, 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.
Makis Tzioras, UK Dementia Research Institute, 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.
Sandra Almeida, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States.
Fen-Biao Gao, Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States.
Michael Marks, Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Christopher J. Donnelly, Department 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, Department of Stem Cell Biology Regenerative Medicine, USC Keck School of Medicine, Los Angeles, CA, United States.
Justin Ichida, Department 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.
Mathew Blurton-Jones, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States.
Tania F. Gendron, Department of Neuroscience, 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.
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.

Document Type

Article

Abstract

While motor and cortical neurons are affected in 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 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, ALS/FTD iPSC-MG mono-cultures form GC repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and 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 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

C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, iPSC-microglia, neuroinflammation

Publication Date

1-1-2023

Publication Title

Frontiers in cellular neuroscience

ISSN

1662-5102

Volume

17

First Page

1179796

PubMed ID

37346371

Digital Object Identifier (DOI)

10.3389/fncel.2023.1179796

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