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

• Published in: Nature communications Vol. 15; no. 1; p. 2497
• Main Authors: Funes, Salome, Jung, Jonathan, Gadd, Del Hayden, Mosqueda, Michelle, Zhong, Jianjun, Shankaracharya, 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/6; 13/100; 13/106; 14/19; 14/56; 14/63; 38/91; 631/378/1689/1285; 631/378/2596/1953; 64/110; 82/58; 82/83; Actin; Amyotrophic lateral sclerosis; Autophagy; Degradation; Humanities and Social Sciences; Lipid metabolism; Lipids; Microglia; multidisciplinary; Mutants; Mutation; Neurodegenerative diseases; Pathogenesis; Phagocytes; Phagocytosis; Pluripotency; Profilin; Rapamycin; Science; Science (multidisciplinary); Stem cells; Toxicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46695-w

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.