SIRT1/FOXO3-mediated autophagy signaling involved in manganese-induced neuroinflammation in microglia

Area of Science:

• Neuroscience
• Environmental Health
• Molecular Biology

Background:

• Manganese (Mn) is an environmental risk factor for Parkinson's disease (PD).
• Mn neurotoxicity involves autophagy dysfunction and neuroinflammation, but the precise molecular mechanisms remain unclear.
• Understanding these mechanisms is crucial for developing therapeutic strategies against Mn-induced parkinsonism.

Purpose of the Study:

• To elucidate the molecular mechanism of Mn-induced neurotoxicity and parkinsonism.
• To investigate the role of SIRT1 in Mn-induced autophagy dysfunction and neuroinflammation.
• To explore the SIRT1/FOXO3-LC3B signaling pathway in Mn neurotoxicity.

Main Methods:

• In vivo and in vitro experiments using cell and animal models.
• Analysis of inflammatory markers (IL-1β, IL-6, TNF-α), autophagy markers (LC3B), and apoptosis.
• Assessment of microglia activation, NF-κB signaling, and neurobehavioral performance.
• Manipulation of SIRT1 expression and activity, and use of autophagy inhibitor 3-MA.

Main Results:

• Mn overexposure led to neuroinflammation, autophagy dysfunction, nerve cell apoptosis, microglia activation, and impaired neurobehavior.
• Mn exposure downregulated SIRT1, which was associated with increased inflammatory responses and impaired autophagy.
• Upregulating SIRT1 alleviated Mn-induced damage, while inhibiting autophagy with 3-MA abolished these benefits.
• Mn interfered with SIRT1-mediated acetylation and nuclear translocation of FOXO3, affecting LC3B transcription.

Conclusions:

• Mn-induced neuroinflammation and autophagy dysfunction are mediated by the downregulation of SIRT1.
• The SIRT1/FOXO3-LC3B autophagy signaling pathway is critically involved in Mn-induced neuroinflammation and neurotoxicity.
• Targeting the SIRT1/FOXO3-LC3B pathway may offer a therapeutic approach for manganese-related neurodegenerative diseases.