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Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia
Salome Funes1,2, Jonathan Jung1,3, Del Hayden Gadd1
1Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
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.
Insights
Mutant profilin-1 (PFN1) causes amyotrophic lateral sclerosis (ALS) by impairing microglia function, specifically lipid metabolism and phagocytosis. Restoring these pathways may offer therapeutic strategies for ALS.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Microglia are crucial in neurodegenerative diseases, but their dysfunction mechanisms are unclear.
- Amyotrophic lateral sclerosis (ALS) is linked to mutations in genes like profilin-1 (PFN1).
Purpose of the Study:
- To investigate how ALS-linked PFN1 mutations affect microglia properties.
- To explore the role of microglial dysfunction in ALS pathogenesis.
Main Methods:
- Utilized human induced pluripotent stem cell-derived microglia-like cells (iMGs) with PFN1 mutations.
- Assessed lipid metabolism, autophagy, phagocytosis, and PFN1 binding affinity for phosphoinositide 3-phosphate (PI3P).
Main Results:
- ALS-PFN1 iMGs showed impaired lipid metabolism, autophagy, and phagocytosis.
- Mutant PFN1 exhibited increased PI3P binding, affecting autophagic and endocytic pathways.
- Rapamycin treatment rescued phagocytic dysfunction in ALS-PFN1 iMGs.
Conclusions:
- Mutant PFN1 gain-of-toxic function disrupts microglial vesicular degradation pathways.
- iMGs are a valuable model for studying neurodegenerative diseases.
- Targeting microglial degradation pathways could be a therapeutic approach for ALS.
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