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Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal
Helena Domínguez-Martín1,2, Elena Gavilán1,2, Celia Parrado1
1Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla (US), 41012 Sevilla, Spain.
Cells
|January 8, 2025
Summary
Proteotoxic stress activates cell-specific autophagy pathways in microglia and neurons. Microglia undergo apoptosis via PERK-CHOP, while neurons activate IRE1α-sXbp1, highlighting distinct cellular responses to stress.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Autophagy is a cellular process with poorly understood roles in different cell types.
- Proteotoxic stress impacts cellular functions, but its specific molecular pathways in CNS cells are unclear.
Purpose of the Study:
- To investigate the role of autophagy in microglia (BV2) and neurons (N2a) under proteotoxic stress.
- To elucidate the distinct molecular pathways and cellular outcomes triggered by proteotoxic stress in these cell types.
Main Methods:
- Proteasome inhibition was used to induce proteotoxic stress in BV2 and N2a cell lines.
- Investigated Unfolded Protein Response (UPR) pathways, including PERK-CHOP and IRE1α-sXbp1.
- Analyzed autophagy activation, cellular proteostasis, phagocytosis, and specific signaling pathways (mTORC2-AKT-FOXO1-β-catenin and PDK1-AKT-FOXO3).
Main Results:
- BV2 cells showed early apoptosis mediated by the PERK-CHOP pathway.
- N2a cells exhibited resistance and activated the IRE1α-sXbp1 pathway.
- Autophagy restored proteostasis in N2a cells but regulated phagocytosis in BV2 cells.
- Distinct signaling pathways (mTORC2-AKT-FOXO1-β-catenin in BV2; PDK1-AKT-FOXO3 in N2a) were activated.
Conclusions:
- Proteotoxic stress induces cell-specific responses in microglia and neurons.
- These distinct responses involve different molecular pathways and lead to varied physiological outcomes.
- Understanding these cell-specific mechanisms is crucial for neurobiology and disease.
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