Abstract
New evidence indicates the involvement of protein degradation dysfunctions in neurodegeneration, innate immunity response and alcohol hepatotoxicity. We recently demonstrated that ethanol increases brain proinflammatory mediators and causes brain damage by activating Toll-like receptor 4 (TLR4) signaling in glia. However, it is uncertain if the ubiquitin-proteasome and autophagy-lysosome pathways are involved in ethanol-induced brain damage and whether the TLR4 response is implicated in proteolytic processes. Using the cerebral cortex of WT and TLR4-knockout mice with and without chronic ethanol treatment, we demonstrate that ethanol induces poly-ubiquitinated proteins accumulation and promotes immunoproteasome activation by inducing the expression of β2i, β5i and PA28α, although it decreases the 20S constitutive proteasome subunits (α2, β5). Ethanol also upregulates mTOR phosphorylation, leading to a downregulation of the autophagy-lysosome pathway (ATG12, ATG5, cathepsin B, p62, LC3) and alters the volume of autophagic vacuoles. Notably, mice lacking TLR4 receptors are protected against ethanol-induced alterations in protein degradation pathways. In summary, the present results provide the first evidence demonstrating that chronic ethanol treatment causes proteolysis dysfunctions in the mouse cerebral cortex and that these events are TLR4 dependent. These findings could provide insight into the mechanisms underlying ethanol-induced brain damage.
Highlights
Digestion through the ubiquitin-proteasome system (UPS) is a selective process responsible for the vast majority of protein degradation in mammalian cells.[7]
There were no significant changes in the Emerging evidence indicates the participation of UPS and autophagy-lysosome pathway (ALP) in both the innate immune response and the pathology of inflammatory and neurodegenerative disorders.[37,38]
We show for the first time that chronic ethanol intake impairs both the UPS and ALP pathways by causing an accumulation of ubiquitinated proteins in the brain, events that might participate in ethanol-induced brain damage and neurodegeneration
Summary
Digestion through the UPS is a selective process responsible for the vast majority of protein degradation in mammalian cells.[7]. Alcohol is a neurotoxic compound and its abuse induces brain damage and can lead to neurodegeneration.[18] the neuropathological processes underlying these effects remain poorly understood, we have demonstrated that ethanol, by activating the brain innate immune system and TLR4 receptors in both cultures of glial cells and in brain,[19,20] induces gliosis, production of cytokines and neuroinflammation, brain damage, myelin derangements and neurodegeneration.[21,22] Elimination of TLR4 receptors abolishes the neuroinflammation and brain damage induced by chronic alcohol intake in mice.[19,20,21] Besides the overactivation of TLRs signaling, dysregulation of proteolytic processes contributes to the pathology of several neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis.[23,24,25] Notably, recent evidence indicates the participation of protein degradation processes in alcoholic liver pathology.[26,27] it is uncertain whether alterations in proteolytic processes are involved in ethanol-induced brain damage and neurodegeneration. The aim of this study is to evaluate if chronic ethanol treatment impairs the UPS and ALP processes in the brain and whether these proteolytic processes are influenced by the innate immune TLR4 receptor
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