The degradation of α--synuclein is limited by dynein to drive the AALP pathway through HDAC6 upon paraquat exposure.

Lewy body disease (LBD), one of the most common neurodegenerative diseases (NDDs), is characterized by excessive accumulation of α-synuclein (α-syn) in neurons. In recent years, environmental factors such as exposure to herbicides and pesticides have been attributed to the development of this condition. While majority of the studies on neurotoxic effects of paraquat (PQ) have focused on α-syn-mediated neuronal damage in the early stages of α-syn accumulation in neurons, efforts to explore the key target for α-syn degradation are limited. Recent research has suggested that histone deacetylase 6 (HDAC6) might possibly regulate amyloid clearance, and that the metabolism of compounds in neurons is also directly affected by axonal transport in neurons. Dynein predominantly mediates reverse transportation of metabolites and uptake of signal molecules and other compounds at the end of axons, which is conducive to the reuse of cell components. However, the role of interaction of dynein with HDAC6 in metabolites transport is still unclear. Therefore, this study aimed to investigate the role of HDAC6 in α-syn accumulation/clearance in neurons and the associated possible influencing factors. The results revealed that HDAC6 could transport ubiquitinated α-syn, bind to dynein, form an aggresome, and relocate to the center of the microtubule tissue, ultimately reducing abnormal accumulation of α-syn. However, PQ treatment resulted in HDAC6 upregulation, causing abnormal aggregation of α-syn. Taken together, these findings indicated that PQ exposure caused abnormal accumulation of α-syn and decreased effective degradation of α-syn by HDAC6-mediated aggresome-autophagy-lysosome pathway.

An approach based on a combination of toxicological experiments and in silico predictions to investigate the adverse outcome pathway (AOP) of paraquat neuro-immunotoxicity.

Paraquat (PQ) exposure is strongly associated with neurotoxicity. However, research on the neurotoxicity mechanisms of PQ varies in terms of endpoints of toxic assessment, resulting in a great challenge to understand the early neurotoxic effects of PQ. In this study, we developed an adverse outcome pathway (AOP) to investigate PQ-induced neuro-immunotoxicity from an immunological perspective, combining of traditional toxicology methods and computer simulations. In vivo, PQ can microstructurally lead to an early synaptic loss in the brain mice, which is a large degree regarded as a main reason for cognitive impairment to mice behavior. Both in vitro and in vivo demonstrated synapse loss is caused by excessive activation of the complement C1q/C3-CD11b pathway, which mediates microglial phagocytosis dysfunction. Additionally, the interaction between PQ and C1q was validated by molecular simulation docking. Our findings extend the AOP framework related to PQ neurotoxicity from a neuro-immunotoxic perspective, highlighting C1q activation as the initiating event for PQ-induced neuro-immunotoxicity. In addition, downstream complement cascades induce abnormal microglial phagocytosis, resulting in reduced synaptic density and subsequent non-motor dysfunction. These findings deepen our understanding of neurotoxicity and provide a theoretical basis for ecological risk assessment of PQ.

A potential mechanism clue to the periodic storm from microglia activation and progressive neuron damage induced by paraquat exposure.

Paraquat (PQ), is characterized by neurotoxicity, which increases the potential risk of Parkinson's disease (PD) exposure in the long-term and low doses. Triggering microglia activation and neuroinflammation is deemed an early event resulting in PD. However, the underlying pathogenesis of PD by PQ is not clear yet. In this article, C57BL/6J mice treated with PQ could successfully act out Parkinson-like. In addition, we observed the fluorescence intensity enhancement of Iba-1 activated microglia with released pro-inflammatory, all ahead of both the damage of dopaminergic neurons in the substantia nigra and corpus striatum of the brain. Surprisingly, the injection of minocycline before PQ for many hours not only can effectively improve the neurobehavioral symptoms of mice but inhibit the activation of microglia and the release of pro-inflammatory substances, even controlling the gradual damage and loss of neurons. A further mechanism of minocycline hampered the expression levels of key signaling proteins PI3K, PDK1, p-AKT, and CD11b (the receptor of microglia membrane recognition), while a large number of inflammatory factors. Our results suggested that the CD11b/PI3K/NOX2 pathway may be a clue that microglia-mediated inflammatory responses and neuronal damage in a PQ-induced abnormal behavior Parkinson-like mouse.