Molecular Mechanism and Regulation of Autophagy and Its Potential Role in Epilepsy

Zhu, Hanxiao; Wang, Wei; Li, Yun

doi:10.3390/cells11172621

Cited by 25 publications

(16 citation statements)

References 305 publications

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“…43 The dynamic regulation of autophagy across the different neuronal compartments in a spaciotemporal manner facilitates specialized neuronal functions. 44 In a study conducted in microglia, the cells were exposed to an acute drop from a high glucose state to a normal glucose state, and this was found to be accompanied by increased LC3BII expression. 45 The findings of this study indicated that increased metabolic stress can pave the way to neuroinflammation and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons

Ramakrishnan,

Srivastava,

Rajan

et al. 2024

Clinical Translational Sci

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Hypoglycemia‐associated autonomic failure (HAAF) is a well‐established complication of diabetes. Although HAAF has serious outcomes such as recurrent morbidity, coma, and death, the mechanisms of HAAF and its pathological components are largely unknown. Our previous studies have revealed that hypoglycemia is associated with the upregulation of an immediate early gene – FOS. In addition, it is documented that glucose deprivation activates neuronal autophagic activities. Therefore, the present study aimed to identify the role of FOS and one of the core components of the autophagy pathway, Beclin‐1 (encoded by the BECN1 gene), in the regulation of autophagic mechanisms in embryonic hypothalamic neurons in response to hypoglycemic conditions. Embryonic Mouse Hypothalamic Cell Line N39 (mHypoE‐N39 or N39) was cultured in reduced concentrations of glucose (2000, 900, 500, and 200 mg/L). Gene and protein expression, as well as immunofluorescence studies on autophagy were conducted under different reduced glucose concentrations in N39 hypothalamic neurons with and without FOS and BECN1 gene knockdowns (KD). The outcomes of the present study have demonstrated a significant increase in autophagosome formation and subsequent lysosomal degradation in the hypothalamic neurons in response to reduced glucose concentrations. This hypoglycemic response appears to be lowered to a similar extent in the FOS KD and BECN1 KD cells, albeit insignificantly from the negative control, is indicative of the involvement of FOS in the autophagic response of hypothalamic neurons to hypoglycemia. Moreover, the KD cells exhibited a change in morphology and reduced cell viability compared with the control cells. Our findings suggest that reduced FOS expression could potentially be associated with impaired autophagic activities that are dependent on BECN1, which could lead to decreased or blunted hypothalamic activation in response to hypoglycemia, and this, in turn, may contribute to the development of HAAF.

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Section: Discussionmentioning

confidence: 99%

Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons

Ramakrishnan,

Srivastava,

Rajan

et al. 2024

Clinical Translational Sci

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“…Moreover, an alteration of the proteins involved in the autophagy process could also be caused by other brain pathological conditions, such as epilepsy [48], ischemic and hemorrhagic stroke [49,50], Alzheimer's disease [51,52], and Parkinson's disease [53][54][55][56]. For example, a LC3-II increase and a LAMP2A decrease have been reported in the substantia nigra of Parkinson's disease models [53], as well as an alteration of GSK-3β and TDP-43 in some forms of dementia [52], and an impairment of LC3-II and p62 in epilepsy [48].…”

Section: Discussionmentioning

confidence: 99%

Old and Promising Markers Related to Autophagy in Traumatic Brain Injury

Livieri

Cuttaia

Vetrini

et al. 2022

IJMS

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Traumatic brain injury (TBI) is one of the first causes of death and disability in the world. Because of the lack of macroscopical or histologic evidence of the damage, the forensic diagnosis of TBI could be particularly difficult. Considering that the activation of autophagy in the brain after a TBI is well documented in literature, the aim of this review is to find all autophagy immunohistological protein markers that are modified after TBI to propose a method to diagnose this eventuality in the brain of trauma victims. A systematic literature review on PubMed following PRISMA 2020 guidelines has enabled the identification of 241 articles. In all, 21 of these were enrolled to identify 24 markers that could be divided into two groups. The first consisted of well-known markers that could be considered for a first diagnosis of TBI. The second consisted of new markers recently proposed in the literature that could be used in combination with the markers of the first group to define the elapsed time between trauma and death. However, the use of these markers has to be validated in the future in human tissue by further studies, and the influence of other diseases affecting the victims before death should be explored.

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“…In a rat model of pilocarpine‐induced epilepsy, activation of the mTOR signaling pathway inhibits neuronal autophagy and avoids neuronal apoptosis, which can prevent acute epilepsy (Liu et al., 2022). Furthermore, autophagy dysfunction exists in epilepsy (Zhu et al., 2022), and the impairment of mTOR‐dependent autophagy has been found to be related to the mechanism by which mTOR overactivation promotes epilepsy (Limanaqi et al., 2020). Rapamycin induces early activation of the autophagy cascade via blockade of mTOR, while activation of mTOR inhibits the formation of autophagosomes (Crino, 2016).…”

Section: The Role Of the Mtor Signaling Pathway In Epilepsymentioning

confidence: 99%

Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

et al. 2023

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Introduction: Epilepsy is one of the most common and serious brain syndromes and has adverse consequences on a patient's neurobiological, cognitive, psychological, and social wellbeing, thereby threatening their quality of life. Some patients with epilepsy experience poor treatment effects due to the unclear pathophysiological mechanisms of the syndrome. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway is thought to play an important role in the onset and progression of some epilepsies.Methods: This review summarizes the role of the mTOR signaling pathway in the pathogenesis of epilepsy and the prospects for the use of mTOR inhibitors. Results:The mTOR pathway functions as a vital mediator in epilepsy development through diverse mechanisms, indicating that the it has great potential as an effective target for epilepsy therapy. The excessive activation of mTOR signaling pathway leads to structural changes in neurons, inhibits autophagy, exacerbates neuron damage, affects mossy fiber sprouting, enhances neuronal excitability, increases neuroinflammation, and is closely associated with tau upregulation in epilepsy. A growing number of studies have demonstrated that mTOR inhibitors exhibit significant antiepileptic effects in both clinical applications and animal models. Specifically, rapamycin, a specific inhibitor of TOR, reduces the intensity and frequency of seizures. Clinical studies in patients with tuberous sclerosis complex have shown that rapamycin has the function of reducing seizures and improving this disease. Everolimus, a chemically modified derivative of rapamycin, has been approved as an added treatment to other antiepileptic medicines. Further explorations are needed to evaluate the therapeutic efficacy andThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Molecular Mechanism and Regulation of Autophagy and Its Potential Role in Epilepsy

Cited by 25 publications

References 305 publications

Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons

Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons

Old and Promising Markers Related to Autophagy in Traumatic Brain Injury

Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

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