The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro

Dulović, Marija; Jovanović, M.; Xilouri, Maria; Stefanis, Leonidas; Harhaji-Trajković, Ljubica; Kravić-Stevović, Tamara; Paunović, Verica; Ardah, Mustafa T.; El-Agnaf, Omar M. A.; Kostić, Vladimir; Marković, Ivanka; Trajkovič, Vladimir

doi:10.1016/j.nbd.2013.11.002

Cited by 111 publications

(72 citation statements)

References 66 publications

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“…AICAR treatment of alpha synuclein over-expressing cells reduced the increase in LC3 II conversion caused by alpha synuclein toxicity and increased cell viability, having a similar effect to metformin (discussed above, [86]). …”

Section: Aicarmentioning

confidence: 91%

“…This is because the m.13051G>A mutant cells grew better in idebenone and we did not see a robust growth advantage to m.3243G>A in metformin under energetic stress up to 72 hours. On the other hand, metformin treatment of cells over expressing alpha synuclein (a major component in many forms of Parkinson's) has proved effective in increasing cell viability and abolished the toxic effects of alpha synucelin [86]. In addition metformin has shown to be protective in other models of Parkinson's [87,88] and Alzheimer's [89].…”

Section: Metforminmentioning

confidence: 99%

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Modulating Mitophagy in Mitochondrial Disease

Dombi

Mortiboys

Poulton

2019

CMC

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Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may effect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

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Section: Aicarmentioning

confidence: 91%

Section: Metforminmentioning

confidence: 99%

Modulating Mitophagy in Mitochondrial Disease

Dombi

Mortiboys

Poulton

2019

CMC

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“…α-synuclein overexpression and elevated extracellular levels of α-synuclein also downregulate AMPK activation in in vitro models, and restoring the AMPK activity reduces α-synuclein toxicity [78].…”

Section: Metforminmentioning

confidence: 99%

Parkinson';s Disease, Diabetes and Cognitive Impairment

Ashraghi¹,

Pagano²,

Polychronis³

et al. 2016

EMI

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Patents published in the last 5 years could be used in novel approaches to Parkinson's treatment by targeting specific pathophysiology proteins, such as Nurr1, PINK1 and NrF2, while patents to improve penetration of the blood brain barrier could allow improved efficacy of existing treatments. Conclusion:Further studies using GLP-1 agonists and DPP-4 inhibitors to treat PD are warranted as they have shown promise.

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“…U ovom istraživanju smo koristili ćelije humanog neuroblastoma SH-SY5Y, koje smo diferentovali pomoću RA do neuronskog fenotipa. Analizom ćelija pomoću svetlosne mikroskopije uz primenu faznog kontrasta uočeni su manja gustina diferentovanih ćelija, kao i znaci izmenjene morfologije ćelija (gubitak tipičnog poligonalnog oblika i pojava dugih nastavaka) (30). Ćelije su tretirane medijumom koji sadrži vanćelijski ASYN, što je uzrokovalo povećanje nivoa markera autofagije, proteina LC3-II i beklin-1, što indirektno pokazuje da vanćelijski ASYN dovodi do indukcije autofagije.…”

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“…Iz ovih rezultata možemo zaključiti da autofagija može da bude mehanizam kojim se ćelija brani od prekomernog nakupljanja ASYN u vanćelijskom prostoru. Dosadašnja istraživanja su pokazala da prekomerna količina ASYN u vanćelijskom prostoru nepovoljno utiče na ćelije neuroblastoma koje su diferentovane u neuronski fenotip (30), kao i da smanjena funkcija lizozomalnog sistema za razgradnju proteina, autofagije, dovodi ne samo do nagomilavanja ASYN unutar ćelija već i do sekrecije ASYN u vanćelijski prostor i prenosa ASYN sa ćelije na ćeliju (31). Štaviše, primena farmakološkog inhibitora autofagije, 3-metiladenina (3-MA), dovodi do nakupljanja ASYN, što potvrđuje nepovoljan efekat inhibicije autofagije i njen značaj u metabolizmu ASYN (32).…”

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The role of autophagy in neurotoxicity caused by extracellular ASYN

Djuranovic¹,

Jeremic²,

Zogović³

et al. 2016

Med podmladak

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Key words:α-synuclein, autophagy, ATG7, SH-SY5Y, neurotoxicityIntroduction: The accumulation of alpha-synuclein (ASYN) in susceptible neurons is considered to be a major contributing factor in pathogenesis of Parkinson's disease. Although ASYN was considered as an intracellular protein, recent data suggest that it can be detected extracellularly. Autophagy plays an important role in ASYN degradation; therefore, impairment of autophagy could be an important contributor to ASYN accumulation. ATG (autophagy-related genes) proteins function at several physiologically continuous steps in autophagy, and ATG7 is considered as essential in autophagosome formation and maturation. Aim: The aim of this study was to investigate the role of autophagy in neurotoxicity, caused by extracellular ASYN. Material and methods: All experiments were conducted in all-trans retinoic acid-differentiated human neuroblastoma SH-SY5Y cells, that were exposed to extracellular ASYN. The presence of extracellular ASYN and the expression of autophagy markers, beclin-1 and LC3-II, were monitored using immunoblotting. Transfection, with small interfering RNA (siRNA), was used to knock down ATG7 gene. Cell viability was assessed using crystal violet dye exclusion assay. Results: Extracellular ASYN caused significant loss of viability in differentiated SH-SY5Y cells, accompanied by the increase in expression of beclin-1 and in conversion of LC3-I to autophagosome-associated LC3-II. The RNA interference-mediated knock-down of ATG7 increased the sensitivity of SH-SY5Y cells to the extracellular ASYN-induced toxicity. Conclusion: Extracellular ASYN caused loss of viability in differentiated SH-SY5Y cells accompanied by autophagy induction. Having in mind that inhibition of autophagy, through ATG7 knock-down increased cell death, we can conclude that autophagy could have a protective role in the harmful effect of extracellular ASYN.

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The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro

Cited by 111 publications

References 66 publications

Modulating Mitophagy in Mitochondrial Disease

Modulating Mitophagy in Mitochondrial Disease

Parkinson';s Disease, Diabetes and Cognitive Impairment

The role of autophagy in neurotoxicity caused by extracellular ASYN

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