Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature communications, 2024-03, Vol.15 (1), p.2497-2497, Article 2497

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.