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Exposure to Manganese Induces Autophagy-Lysosomal Pathway Dysfunction-Mediated Tauopathy by Activating the cGAS-STING
Xin Zhang1, Jingjing Liu1, Shiyin Zhong1
1Department of Toxicology, School of Public Health, Lanzhou University, Gansu 730000, China.
Abstract:
Manganese (Mn) exposure leads to pathological accumulation of Tau-associated neurodegenerative disease and has become a major public health concern. However, the precise mechanism underlying this effect remains unclear. Here, the mechanism by which Mn induces dysfunction of autophagy-lysosomal pathway-mediated tauopathy by activating the cGAS-STING pathway was explored both in vitro and in vivo. Mn exposure induced tauopathy in microglia and in mice while activating the cGAS-STING pathway, inducing type I interferon production, and impairing the degradation function of the autophagy-lysosomal pathway. Importantly, inactivation of the cGAS-STING pathway rescued the degradation activity of the autophagy-lysosomal pathway, while tauopathy was markedly attenuated, as shown in both cGAS-knockout and STING-knockout BV2 microglia and in mice. Moreover, the autophagy inhibitor 3-methyladenine (3-MA) restored the impaired degradation activity of the autophagy-lysosomal pathway by inactivating the cGAS-STING pathway, thereby clearing Tau aggregation. Taken together, these results indicate that Mn exposure induces tauopathy by impairing the function of the autophagy-lysosomal pathway through the activation of the cGAS-STING pathway. Thus, this study identifies a novel mechanism by which Mn exposure induces Tau aggregation, which in turn triggers potential neurotoxicity, providing a foundation for future drug target research.
Insights
Manganese exposure causes neurodegeneration by disrupting the autophagy-lysosomal pathway via the cGAS-STING pathway, leading to Tau aggregation and potential neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese (Mn) exposure is linked to neurodegenerative diseases and Tau pathology.
- The precise mechanisms by which Mn induces neurotoxicity remain incompletely understood.
- Dysfunction of the autophagy-lysosomal pathway is implicated in neurodegenerative processes.
Purpose of the Study:
- To elucidate the mechanism by which Mn exposure induces autophagy-lysosomal pathway dysfunction and tauopathy.
- To investigate the role of the cGAS-STING pathway in Mn-induced neurotoxicity.
- To explore potential therapeutic targets for mitigating Mn-induced neurodegeneration.
Main Methods:
- In vitro studies using BV2 microglia and in vivo studies using mice exposed to Manganese.
- Assessment of tauopathy, cGAS-STING pathway activation, type I interferon production, and autophagy-lysosomal pathway function.
- Utilized cGAS-knockout and STING-knockout models, and employed the autophagy inhibitor 3-methyladenine (3-MA).
Main Results:
- Mn exposure activated the cGAS-STING pathway, induced type I interferon, and impaired autophagy-lysosomal pathway degradation in microglia and mice.
- Inactivation of the cGAS-STING pathway (via knockout or 3-MA) restored autophagy-lysosomal function and attenuated Mn-induced tauopathy.
- Clearing of Tau aggregation was observed upon restoration of autophagy-lysosomal pathway function.
Conclusions:
- Mn exposure induces tauopathy by activating the cGAS-STING pathway, leading to impaired autophagy-lysosomal pathway function.
- The cGAS-STING pathway is a critical mediator of Mn-induced neurotoxicity and Tau aggregation.
- Targeting the cGAS-STING pathway presents a potential therapeutic strategy for Mn-induced neurodegenerative conditions.
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