Melatonin‐induced autophagy protects against human prion protein‐mediated neurotoxicity

Jeong, Jae‐Kyo; Moon, Myung‐Hee; Lee, You-Jin; Seol, Jae‐Won; Park, Sang-Youel

doi:10.1111/j.1600-079x.2012.00980.x

Cited by 61 publications

(58 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results strongly suggest the contribution of the melatonin receptor in ovine classical scrapie pathology, even in the early phase of the disease and in different brain regions; therefore, melatonin may be a good candidate target for future prion disease therapies. In accordance with our suggestion, a recent report has shown that melatonin-induced autophagy protects against prion protein-mediated neurotoxicity [77]. …”

Section: Discussionsupporting

confidence: 92%

Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

Filali

Vidal

Bolea

et al. 2013

Vet Res

View full text Add to dashboard Cite

The molecular pathogenic mechanisms of prion diseases are far from clear. Genomic analyses have revealed genetic biomarkers potentially involved in prion neuropathology in naturally scrapie-infected sheep, a good animal model of infectious prionopathies. However, these biomarkers must be validated in independent studies at different stages of the disease. The gene and protein expression profiles and protein distribution of six potential genetic biomarkers (i.e., CAPN6, COL1A2, COL3A1, GALA1, MT2A and MTNR1B) are presented here for both the early and terminal stages of scrapie in five different brain regions. Gene transcription changes were confirmed in the medulla oblongata, and the expression profiles were generally similar in other central nervous system regions. The changes were more substantial in clinical animals compared to preclinical animals. The expression of the CAPN6 protein increased in the spinal cord and cerebellum of the clinical and preclinical brains. The distribution of the GALA1 was identified in glial cells from the cerebellum of scrapie-infected animals, GALA1 protein expression was increased in clinical animals in the majority of regions, and the increase of MT2A was in agreement with previous reports. The downregulation of MTNR1B was especially marked in the Purkinje cells. Finally, although collagen genes were downregulated the protein immunostaining did not reveal significant changes between the scrapie-infected and control animals. In conclusion, this study of gene transcription and protein expression and distribution confirm CAPN6, GALA1, MTNR1B and MT2A as potential targets for further prion disease research.

show abstract

Section: Discussionsupporting

confidence: 92%

Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

Filali

Vidal

Bolea

et al. 2013

Vet Res

View full text Add to dashboard Cite

show abstract

“…Although during the last decade different studies have related melatonin with autophagy regulation in different disease models, like cardiac and brain ischemia or subarachnoid hemorrhage, kainic acid–induced toxicity, prion peptide–induced toxicity, Parkinson's disease, traumatic brain injury, or aging models, little is known about its implication in AD, and more specifically in tauopathies. Melatonin is widely known to regulate the autophagy‐lysosome machinery at very different levels .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Luengo¹,

Buendía

Fernández‐Mendívil³

et al. 2019

Journal of Pineal Research

View full text Add to dashboard Cite

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.

show abstract

“…Furthermore, some of the apoptotic pathway genes we detected among the potential RORa target genes were shown to be regulated by melatonin. While Bcl2 pathway-related gene Atg5 was shown to be responsible for neuroprotective role of melatonin (30), cytochrome c pathway-related gene Nlrp3 was found to be involved in anti-inflammatory role of melatonin (31). Though the latter study focused on inflammation and not apoptosis, it revealed the involvement of RORa and melatonin in Nlrp3-NFkappaB pathway.…”

Section: Discussionmentioning

confidence: 99%

Role of simvastatin and RORα activity in the macrophage apoptotic pathway

Çoban

Güleç

Selçuk³

et al. 2017

Anatol J Cardiol

View full text Add to dashboard Cite

Objective: Atherosclerosis is a chronic inflammatory condition and is one of the main causes of death worldwide. Macrophages play important roles in the formation of atherosclerotic plaques. Apoptosis is progressively observed while plaques develop, although the precise mechanisms and outcomes of apoptosis in atherosclerosis development and progression are still contradictory. This study was conducted to explore the effects of simvastatin and retinoic acid receptor-related orphan receptor alpha (RORa) ligands on apoptosis in human acute monocytic leukemia (THP-1) macrophage cells. Methods: Briefly, the occupancy of RORa in the promoter regions of apoptotic pathway genes was demonstrated in THP-1 cell lines using chromatin immunoprecipitation (ChIP) analysis. In order to modulate RORa activity, THP-1 macrophage cells were treated with specific ligands (CPG52608 and SR1001) and then viability as well as count of THP-1 macrophage cells were analyzed. Results: We observed that simvastatin and both RORa ligands had a tendency to decrease THP-1 macrophage cell viability in culture. When compared with non-treated controls, simvastatin significantly decreased cell viability (p=0.04) and cell count (p=0.03). However, this negative effect of simvastatin seemed to be partly prevented by RORa ligands. In addition, bioinformatics analysis of ChIP-on-chip data demonstrated that several genes that are involved in the apoptotic pathway were likely RORa target genes. These genes were involved in the regulation of apoptosis through various pathways. Conclusion: In summary, our study suggest that simvastatin-mediated macrophage apoptosis might be modulated by SR1001 administration. However, involvement of RORa in this modulation through potential apoptotic target genes remains elusive.

show abstract

Melatonin‐induced autophagy protects against human prion protein‐mediated neurotoxicity

Cited by 61 publications

References 43 publications

Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Role of simvastatin and RORα activity in the macrophage apoptotic pathway

Contact Info

Product

Resources

About