Dynamic expression of autophagy-related factors in autoimmune encephalomyelitis and exploration of curcumin therapy

Yuan, Baoyu; Sun, Menghong; Li, Xiaoling; Liu, Zhenxing; Wang, Manxia

doi:10.1016/j.jneuroim.2019.577067

Cited by 24 publications

(16 citation statements)

References 25 publications

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“…In addition, in experimental autoimmune encephalomyelitis (EAE), an MS mouse model, LC3 and BECLIN1 protein levels were reduced while those of p62/SQSTM1 were increased in the spinal cords of these animals. Moreover, inhibition of mTORC1 ameliorated disease severity (Boyao et al, 2019), suggesting that autophagy is negatively affected in EAE mice. Inhibition of autophagy can also result in the accumulation of damaged mitochondria and the production of ROS (Chen et al, 2008;Hassanpour et al, 2020), which both contribute to the demyelination process in MS. Another approach to enhance autophagy is through caloric restriction, where cycles of a fasting-mimicking diet are applied, and this regime has been shown to ameliorate disease severity and stimulates remyelination in both EAE mice and relapsing-remitting MS patients (Choi et al, 2016).…”

Section: Autophagy and Msmentioning

confidence: 99%

Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

Misrielal

Mauthe

Reggiori

et al. 2020

Front. Cell. Neurosci.

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Multiple sclerosis (MS) is a complex auto-immune disorder of the central nervous system (CNS) that involves a range of CNS and immune cells. MS is characterized by chronic neuroinflammation, demyelination, and neuronal loss, but the molecular causes of this disease remain poorly understood. One cellular process that could provide insight into MS pathophysiology and also be a possible therapeutic avenue, is autophagy. Autophagy is an intracellular degradative pathway essential to maintain cellular homeostasis, particularly in neurons as defects in autophagy lead to neurodegeneration. One of the functions of autophagy is to maintain cellular homeostasis by eliminating defective or superfluous proteins, complexes, and organelles, preventing the accumulation of potentially cytotoxic damage. Importantly, there is also an intimate and intricate interplay between autophagy and multiple aspects of both innate and adaptive immunity. Thus, autophagy is implicated in two of the main hallmarks of MS, neurodegeneration, and inflammation, making it especially important to understand how this pathway contributes to MS manifestation and progression. This review summarizes the current knowledge about autophagy in MS, in particular how it contributes to our understanding of MS pathology and its potential as a novel therapeutic target.

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Section: Autophagy and Msmentioning

confidence: 99%

Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

Misrielal

Mauthe

Reggiori

et al. 2020

Front. Cell. Neurosci.

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“…Lower LC3-I/II and beclin-1 expression with consequent impaired autophagy were shown to occur in the spinal cord of EAE mice ( 53 , 54 ) and induction of autophagy via the Cannabinoid Receptor 2 (CBR2) ameliorated EAE ( 55 ). Furthermore, it is reported that the expression of ATG5 is elevated in EAE ( 56 ), which is not corroborated by our findings and can likely be explained by differences in the analyzed samples and different stages of disease (purified T cells from EAE mice and postmortem brain tissue versus spinal cord as presented in this study).…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord

et al. 2021

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Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.

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“…Additionally, blocking the activity of the RBP HuR in EAE animals improved motor function and decreased demyelination, suggesting that RBPs contribute to clinical disease severity in EAE [132]. Furthermore, rapamycin, an autophagy inducer, that has been shown to correct TDP-43 mislocalization phenotypes and restore nuclear localization, reduced EAE severity, neuronal damage, and demyelination [133]. Finally, in EAE, poly ADP-ribose (PAR), a factor required for SG assembly [105,106], was found to be elevated in neurons, astrocytes, oligodendrocytes, and microglial in and around demyelinated plaques, suggesting increased SG formation, a feature heavily associated with dysfunctional RBPs [116].…”

Section: Evidence In Neuronsmentioning

confidence: 99%

The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models

Libner

Salapa

Levin

2020

IJMS

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Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs.

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Dynamic expression of autophagy-related factors in autoimmune encephalomyelitis and exploration of curcumin therapy

Cited by 24 publications

References 25 publications

Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord

The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models

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