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

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

doi:10.1038/s41467-024-46695-w

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

Nat Commun. 2024 Mar 20;15(1):2497. doi: 10.1038/s41467-024-46695-w.

Authors

Salome Funes^#^{1

2}, Jonathan Jung^#^{1

3}, Del Hayden Gadd¹, Michelle Mosqueda^{4

5}, Jianjun Zhong^{1

6}, Shankaracharya¹, Matthew Unger^{5

7}, Karly Stallworth¹, Debra Cameron¹, Melissa S Rotunno¹, Pepper Dawes^{8

9}, Megan Fowler-Magaw^{1

3}, Pamela J Keagle¹, Justin A McDonough¹⁰, Sivakumar Boopathy^{1

5}, Miguel Sena-Esteves^{1

11}, Jeffrey A Nickerson¹², Cathleen Lutz¹³, William C Skarnes¹⁰, Elaine T Lim^{3

8

9}, Dorothy P Schafer^{3

14}, Francesca Massi^{4

5}, John E Landers^{1

3}, Daryl A Bosco^{15

16

17

18

19}

Affiliations

¹ Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
² Translational Science Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
³ Neuroscience Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁴ Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁵ Biochemistry and Molecular Biotechnology Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁶ Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
⁷ Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁸ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁹ Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
¹⁰ The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
¹¹ Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
¹² Department of Pediatrics, University of Massachusetts Medical School, Worcester, Worcester, MA, 01605, USA.
¹³ The Jackson Laboratory Center for Precision Genetics, Rare Disease Translational Center, Bar Harbor, ME, 04609, USA.
¹⁴ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
¹⁵ Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Daryl.Bosco@umassmed.edu.
¹⁶ Translational Science Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Daryl.Bosco@umassmed.edu.
¹⁷ Neuroscience Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Daryl.Bosco@umassmed.edu.
¹⁸ Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Daryl.Bosco@umassmed.edu.
¹⁹ Biochemistry and Molecular Biotechnology Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Daryl.Bosco@umassmed.edu.

^# Contributed equally.

Abstract

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.

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Humans
Induced Pluripotent Stem Cells* / metabolism
Microglia / metabolism
Mutation
Neurodegenerative Diseases*
Profilins / metabolism

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

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