Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

作者全名："Funes, Salome; Jung, Jonathan; Gadd, Del Hayden; Mosqueda, Michelle; Zhong, Jianjun; Unger, Matthew; Stallworth, Karly; Cameron, Debra; Rotunno, Melissa S.; Dawes, Pepper; Fowler-Magaw, Megan; Keagle, Pamela J.; McDonough, Justin A.; Boopathy, Sivakumar; Sena-Esteves, Miguel; Nickerson, Jeffrey A.; Lutz, Cathleen; Skarnes, William C.; Lim, Elaine T.; Schafer, Dorothy P.; Massi, Francesca; Landers, John E.; Bosco, Daryl A."

作者地址："[Funes, Salome; Jung, Jonathan; Gadd, Del Hayden; Zhong, Jianjun; Stallworth, Karly; Cameron, Debra; Rotunno, Melissa S.; Fowler-Magaw, Megan; Keagle, Pamela J.; Boopathy, Sivakumar; Sena-Esteves, Miguel; Landers, John E.; Bosco, Daryl A.] Univ Massachusetts, Chan Med Sch, Dept Neurol, Worcester, MA 01605 USA; [Funes, Salome; Bosco, Daryl A.] Univ Massachusetts, Chan Med Sch, Morningside Grad Sch Biomed Sci, Translat Sci Program, Worcester, MA 01605 USA; [Jung, Jonathan; Fowler-Magaw, Megan; Lim, Elaine T.; Schafer, Dorothy P.; Landers, John E.; Bosco, Daryl A.] Univ Massachusetts, Morningside Grad Sch Biomed Sci, Neurosci Program, Chan Med Sch, Worcester, MA 01605 USA; [Mosqueda, Michelle; Massi, Francesca; Bosco, Daryl A.] Univ Massachusetts, Dept Biochem & Mol Biotechnol, Chan Med Sch, Worcester, MA 01605 USA; [Mosqueda, Michelle; Unger, Matthew; Boopathy, Sivakumar; Massi, Francesca; Bosco, Daryl A.] Univ Massachusetts, Morningside Grad Sch Biomed Sci, Biochem & Mol Biotechnol Program, Chan Med Sch, Worcester, MA 01605 USA; [Zhong, Jianjun] Chongqing Med Univ, Dept Neurosurg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Unger, Matthew] Univ Massachusetts, Chan Med Sch, Dept Microbiol & Physiol Syst, Worcester, MA 01605 USA; [Dawes, Pepper; Lim, Elaine T.] Univ Massachusetts, Chan Med Sch, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA; [Dawes, Pepper; Lim, Elaine T.] Univ Massachusetts, Dept Genom & Computat Biol, Chan Med Sch, Worcester, MA 01605 USA; [McDonough, Justin A.; Skarnes, William C.] Jackson Lab Genom Med, Farmington, CT 06032 USA; [Sena-Esteves, Miguel] Univ Massachusetts, Chan Med Sch, Horae Gene Therapy Ctr, Worcester, MA 01605 USA; [Nickerson, Jeffrey A.] Univ Massachusetts, Med Sch, Dept Pediat, Worcester, MA 01605 USA; [Lutz, Cathleen] Ctr Precis Genet, Rare Dis Translat Ctr, Jackson Lab, Rare Dis Translat Ctr, Bar Harbor, ME 04609 USA; [Schafer, Dorothy P.] Univ Massachusetts, Chan Med Sch, Brudnick Neuropsychiat Res Inst, Dept Neurobiol, Worcester, MA 01605 USA"

通信作者："Bosco, DA (通讯作者)，Univ Massachusetts, Chan Med Sch, Dept Neurol, Worcester, MA 01605 USA.; Bosco, DA (通讯作者)，Univ Massachusetts, Chan Med Sch, Morningside Grad Sch Biomed Sci, Translat Sci Program, Worcester, MA 01605 USA.; Bosco, DA (通讯作者)，Univ Massachusetts, Morningside Grad Sch Biomed Sci, Neurosci Program, Chan Med Sch, Worcester, MA 01605 USA.; Bosco, DA (通讯作者)，Univ Massachusetts, Dept Biochem & Mol Biotechnol, Chan Med Sch, Worcester, MA 01605 USA.; Bosco, DA (通讯作者)，Univ Massachusetts, Morningside Grad Sch Biomed Sci, Biochem & Mol Biotechnol Program, Chan Med Sch, Worcester, MA 01605 USA."

来源：NATURE COMMUNICATIONS

ESI学科分类：　

WOS号：WOS:001191901500014

JCR分区：Q1

影响因子：14.7

年份：2024

卷号：15

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders. Mutations in profilin 1 (PFN1), which modulates actin dynamics, are associated with ALS. Here the authors show that expression of ALS-PFN1 is sufficient to induce deficits in human microglia-like cells, including impaired phagocytosis and lipid metabolism, and that gain-of-function interactions between ALS-PFN1 and PI3P may underlie these deficits."

基金机构："Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) [R01 NS108769, R21 NS120126]; NIH/NINDS [R01GM137529, NIMH-R01MH113743, NINDS-R01NS117533, NIA-RF1AG068281, U54OD020351]; NIH/NIGMS [W81XWH202071/PRARP]; Department of Defense; Angel Fund for ALS research; Robert Packard Center for ALS Research; Dan and Diane Riccio Fund for Neuroscience"

基金资助正文："We are grateful to Dr. Michael Ward (NINDS, MD) for providing the WTC11 iPSC line with the hNIL cassette, Dr. Jeffery Kelly (the Scripps Research Institute, CA) and his lab for providing Rapamycin and advice, Drs. Yen-Chen Lin (UMass Chan) and Desiree Baron (UMass Chan) for help with iPSC culture, Dr. Anthony Giampetruzzi (UMass Chan) for help with the Cytation 5, Dr. Travis Faust for advice on mouse studies, the UMass Chan Mass spectrometry Facility for the proteomics experiments, and the UMass Chan Transgenic Animal Modeling Core for in vitro fertilization of mutant PFN1 mice, the Cellular Engineering Service at The Jackson Laboratory for expert assistance with gene-editing of iPSCs described in this manuscript. D.A.B. is supported by the NIH/NINDS (R01 NS108769, R21 NS120126), NIH/NIGMS (R01GM137529, R01 GM147677), the Department of Defense (W81XWH202071/PRARP), the Angel Fund for ALS research, the Radala Foundation and the Robert Packard Center for ALS Research. This project has also been supported by the Dan and Diane Riccio Fund for Neuroscience (UMass Chan; to D.A.B. and D.P.S.) and NIH/NIGMS R01GM137529 (F.M. and D.A.B.). We are also grateful for the following support: NIMH-R01MH113743 (D.P.S.); NINDS-R01NS117533 (D.P.S.); NIA-RF1AG068281(D.P.S.); U54OD020351 (to the Jackson Laboratory Center for Precision Genetics, C.L.)."