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 and Daryl A. Bosco ()
Additional contact information
Salome Funes: University of Massachusetts Chan Medical School
Jonathan Jung: University of Massachusetts Chan Medical School
Del Hayden Gadd: University of Massachusetts Chan Medical School
Michelle Mosqueda: University of Massachusetts Chan Medical School
Jianjun Zhong: University of Massachusetts Chan Medical School
Shankaracharya: University of Massachusetts Chan Medical School
Matthew Unger: University of Massachusetts Chan Medical School
Karly Stallworth: University of Massachusetts Chan Medical School
Debra Cameron: University of Massachusetts Chan Medical School
Melissa S. Rotunno: University of Massachusetts Chan Medical School
Pepper Dawes: University of Massachusetts Chan Medical School
Megan Fowler-Magaw: University of Massachusetts Chan Medical School
Pamela J. Keagle: University of Massachusetts Chan Medical School
Justin A. McDonough: The Jackson Laboratory for Genomic Medicine
Sivakumar Boopathy: University of Massachusetts Chan Medical School
Miguel Sena-Esteves: University of Massachusetts Chan Medical School
Jeffrey A. Nickerson: University of Massachusetts Medical School, Worcester
Cathleen Lutz: Rare Disease Translational Center
William C. Skarnes: The Jackson Laboratory for Genomic Medicine
Elaine T. Lim: University of Massachusetts Chan Medical School
Dorothy P. Schafer: University of Massachusetts Chan Medical School
Francesca Massi: University of Massachusetts Chan Medical School
John E. Landers: University of Massachusetts Chan Medical School
Daryl A. Bosco: University of Massachusetts Chan Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46695-w

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