Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils

Zadali, Ramin; Ghareghozloo, Ebrahim Rostampour; Ramezani, Mohammad; Hassani, Vahid; Rafiei, Yasin; Chiyaneh, Shiva  Mohammadi; Meratan, Ali Akbar

doi:10.3791/59883-v

Cited by 5 publications

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“…Maximal efforts were made to minimize suffering and detrimental effects to the rats by sharpening the guillotine blades and applying resolute and swift movements of the blade. All reagents for mitochondrial isolation were prepared according to Sims protocol 71 and Zadali et al 72 . Decapitation and brain removal of male rats was performed according to Sims protocol 71 .…”

Section: Methodsmentioning

confidence: 99%

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Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes

Zohoorian-Abootorabi

Meratan

Jafarkhani

et al. 2023

Sci Rep

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The interplay between α-synuclein (α-syn) and catechols plays a central role in Parkinson’s disease. This may be related to the modulating effects of catechols on the various aspects of α-syn fibrillization. Some of these effects may be attributed to the membrane-binding properties of the protein. In this work, we compare the effect of some catechols, including dopamine, epinephrine, DOPAL, and levodopa in micromolar concentrations, on the in vitro cytotoxicity of α-syn fibrils on human neuroblastoma SH-SY5Y cells. The study was followed by comparing the interactions of resulting structures with rat brain mitochondria used as an in vitro biological model. The obtained results demonstrate that catechols-induced structures have lost their cytotoxicity mimicking apoptotic cell death mediated by α-syn aggregates in different proportions. Moreover, α-syn fibrils-induced mitochondrial dysfunction, evaluated by a range of biochemical assays, was modulated by catechols-modified α-syn oligomers in different manners, as levodopa and DOPAL demonstrated the maximal and minimal effects, respectively. The plausible mechanism causing the inhibition of α-syn cytotoxic fibrillization and mitochondrial dysfunction by catechols is discussed. Taken together, we propose that catechols can prevent the cytotoxic assembly of α-syn and its destructive effects on mitochondria at various stages, suggesting that decreased levels of catechols in dopaminergic neurons might accelerate the α-syn cytotoxicity and mitochondrial dysfunction implicating Parkinson’s disease.

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Section: Methodsmentioning

confidence: 99%

“…All centrifugation steps were carried out at 4 °C. Mitochondrial membrane integrity was confirmed by measuring the malate dehydrogenase (MDH) activity in isolated mitochondria before and after membrane disruption by Triton X-100 72 .…”

Section: Methodsmentioning

confidence: 99%

Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes

Zohoorian-Abootorabi

Meratan

Jafarkhani

et al. 2023

Sci Rep

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“…Mitochondria from rat brains were isolated exactly according to the protocol described by Zadali et al 66 Mitochondrial membrane integrity was confirmed by measuring malate dehydrogenase activity determination in isolated mitochondria before and after membrane disruption by Triton X-100. 66 The total protein concentration was determined using the Bradford assay. 62 The membrane potential of brain mitochondria was determined using the membrane potential sensitive fluorogenic dye rhodamine 123.…”

Section: ■ Conclusionmentioning

confidence: 99%

Neuroprotective Effect of Propolis Polyphenol-Based Nanosheets in Cellular and Animal Models of Rotenone-Induced Parkinson’s Disease

Mamashli

Meratan

Ghasemi

et al. 2023

ACS Chem. Neurosci.

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Considering the central role of oxidative stress in the onset and progress of Parkinson’s diseases (PD), search for compounds with antioxidant properties has attracted a growing body of attention. Here, we compare the neuroprotective effect of bulk and nano forms of the polyphenolic fraction of propolis (PFP) against rotenone-induced cellular and animal models of PD. Mass spectrometric analysis of PFP confirmed the presence of multiple polyphenols including kaempferol, naringenin, coumaric acid, vanillic acid, and ferulic acid. In vitro cellular experiments indicate the improved efficiency of the nano form, compared to the bulk form, of PFP in attenuating rotenone-induced cytotoxicity characterized by a decrease in cell viability, release of lactate dehydrogenase, increased ROS generation, depolarization of the mitochondrial membrane, decreased antioxidant enzyme activity, and apoptosis induction. In vivo experiments revealed that while no significant neuroprotection was observed relating to the bulk form, PFP nanosheets were very effective in protecting animals, as evidenced by the improved behavioral and neurochemical parameters, including decreased lipid peroxidation, increased GSH content, and antioxidant enzyme activity enhancement. We suggest that improved neuroprotective effects of PFP nanosheets may be attributed to their increased water solubility and enrichment with oxygen-containing functional groups (such as OH and COOH), leading to increased antioxidant activity of these compounds.

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“…A biochemical study revealed that glycation of α-synuclein reduces its binding to synaptic-like vesicles thus impacting on fusion (Uceda et al, 2022). α-Synuclein promotes the fusion of vesicles with the plasma membrane, it is involved in the homeostasis of synaptic vesicles during the neurotransmission (Vargas et al, 2014), and it is able to regulate release of vesicle from the presynaptic pools (Zadali et al, 2019;Yoo et al, 2022), rendering this pathway as a candidate for causing synaptic dysfunction in mammalian neurons. There is general consensus that AGEs are responsible for synaptopathologies, AGEs causes a suppression of hippocampal long-term potentiation (Zhang et al, 2014), memory impairments (Li X. H. et al, 2012) and indirect evidence suggests that the receptor for AGE (RAGE) contributes to synaptic dysfunction seen in AD (Criscuolo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster

Stone

Cujic²,

Rowlett³

et al. 2023

Front. Synaptic Neurosci.

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IntroductionNumerous neurodegenerative diseases are associated with neuronal dysfunction caused by increased redox stress, often linked to aberrant production of redox-active molecules such as nitric oxide (NO) or oxygen free radicals. One such protein affected by redox-mediated changes is the glycolytic enzyme triose-phosphate isomerase (TPI), which has been shown to undergo 3-nitrotyrosination (a NO-mediated post-translational modification) rendering it inactive. The resulting neuronal changes caused by this modification are not well understood. However, associated glycation-induced cytotoxicity has been reported, thus potentially causing neuronal and synaptic dysfunction via compromising synaptic vesicle recycling.MethodsThis work uses Drosophila melanogaster to identify the impacts of altered TPI activity on neuronal physiology, linking aberrant TPI function and redox stress to neuronal defects. We used Drosophila mutants expressing a missense allele of the TPI protein, M81T, identified in a previous screen and resulting in an inactive mutant of the TPI protein (TPIM81T, wstd1). We assessed synaptic physiology at the glutamatergic Drosophila neuromuscular junction (NMJ), synapse morphology and behavioural phenotypes, as well as impacts on longevity.ResultsElectrophysiological recordings of evoked and spontaneous excitatory junctional currents, alongside high frequency train stimulations and recovery protocols, were applied to investigate synaptic depletion and subsequent recovery. Single synaptic currents were unaltered in the presence of the wstd1 mutation, but frequencies of spontaneous events were reduced. Wstd1 larvae also showed enhanced vesicle depletion rates at higher frequency stimulation, and subsequent recovery times for evoked synaptic responses were prolonged. A computational model showed that TPI mutant larvae exhibited a significant decline in activity-dependent vesicle recycling, which manifests itself as increased recovery times for the readily-releasable vesicle pool. Confocal images of NMJs showed no morphological or developmental differences between wild-type and wstd1 but TPI mutants exhibited learning impairments as assessed by olfactory associative learning assays.DiscussionOur data suggests that the wstd1 phenotype is partially due to altered vesicle dynamics, involving a reduced vesicle pool replenishment, and altered endo/exocytosis processes. This may result in learning and memory impairments and neuronal dysfunction potentially also presenting a contributing factor to other reported neuronal phenotypes.

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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils

Cited by 5 publications

References 0 publications

Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes

Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes

Neuroprotective Effect of Propolis Polyphenol-Based Nanosheets in Cellular and Animal Models of Rotenone-Induced Parkinson’s Disease

Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster

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