Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model
Zhenqing Liu,
Jianfei Chao,
Cheng Wang,
Guihua Sun,
Daniel Roeth,
Wei Liu,
Xianwei Chen,
Li Li,
E Tian,
Lizhao Feng,
Hayk Davtyan,
Mathew Blurton-Jones,
Markus Kalkum,
Yanhong Shi
Affiliations
Zhenqing Liu
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Jianfei Chao
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Cheng Wang
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Guihua Sun
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Daniel Roeth
Department of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Wei Liu
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Department of Immunology, Hebei Medical University, Shijiazhuang, Hebei 050017, China
Xianwei Chen
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Li Li
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
E Tian
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Lizhao Feng
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Hayk Davtyan
Department of Neurobiology & Behavior, Institute for Memory Impairments & Neurological Disorders and Sue & Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA
Mathew Blurton-Jones
Department of Neurobiology & Behavior, Institute for Memory Impairments & Neurological Disorders and Sue & Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA
Markus Kalkum
Department of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Yanhong Shi
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Corresponding author
Summary: The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer’s disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the “C” or “T” allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the “C” allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk “C” allele carriers.
