Document Type
Article
Publication Date
3-20-2024
Original Citation
Funes S,
Jung J,
Gadd D,
Mosqueda M,
Zhong J,
Shankaracharya ,
Unger M,
Stallworth K,
Cameron D,
Rotunno M,
Dawes P,
Fowler-Magaw M,
Keagle P,
McDonough J,
Boopathy S,
Sena-Esteves M,
Nickerson J,
Lutz C,
Skarnes W,
Lim E,
Schafer D,
Massi F,
Landers J,
Bosco D.
Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia. Nat Commun. 2024;15(1):2497
Keywords
JGM, JMG, SS1, Humans, Amyotrophic Lateral Sclerosis, Microglia, Induced Pluripotent Stem Cells, Profilins, Neurodegenerative Diseases, Mutation
JAX Source
Nat Commun. 2024;15(1):2497
ISSN
2041-1723
PMID
38509062
DOI
https://doi.org/10.1038/s41467-024-46695-w
Grant
U54OD020351 (to the Jackson Laboratory Center for Precision Genetics, C.L.)
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.
Comments
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