Molecular mechanism of olesoxime-mediated neuroprotection through targeting α-synuclein interaction with mitochondrial VDAC.
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ABSTRACT:
SUBMITTER: Rovini A
PROVIDER: S-EPMC7244372 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alpha-Synuclein (αSyn) is a protein whose function is still debated, as well as its role in modulation of mitochondrial function in both physiological and pathological conditions. Mitochondrial porins or Voltage-Dependent Anion Channel (VDAC) proteins are the main gates for ADP/ATP and various substrates towards the organelle. Furthermore, they act as a mitochondrial hub for many cytosolic proteins, including αSyn. This review analyzes the main aspects of αSyn-mitochondria interaction, focusing on the role of VDAC and its emerging involvement in the pathological processes.
| S-EPMC8170894 | biostudies-literature
Project description:Ethnopharmacological relevanceHolothuria (Metriatyla) scabra Jaeger (H. scabra), sea cucumber, is the marine organism that has been used as traditional food and medicine to gain the health benefits since ancient time. Although our recent studies have shown that crude extracts from H. scabra exhibited neuroprotective effects against Parkinson's disease (PD), the underlying mechanisms and bioactive compounds are still unknown.Aim of the studyIn the present study, we examined the efficacy of purified compounds from H. scabra and their underlying mechanism on α-synuclein degradation and neuroprotection against α-synuclein-mediated neurodegeneration in a transgenic Caenorhabditis elegans PD model.Material and methodsThe H. scabra compounds (HSEA-P1 and P2) were purified and examined for their toxicity and optimal dose-range by food-clearance and lifespan assays. The α-synuclein degradation and neuroprotection against α-synuclein-mediated neurodegeneration were determined using transgenic C. elegans model, Punc-54::α-syn and Pdat-1:: α-syn; Pdat-1::GFP, respectively, and then further investigated by determining the behavioral assays including locomotion rate, basal slowing rate, ethanol avoidance, and area-restricted searching. The underlying mechanisms related to autophagy were clarified by quantitative PCR and RNAi experiments.ResultsOur results showed that HSEA-P1 and HSEA-P2 significantly diminished α-synuclein accumulation, improved motility deficits, and recovered the shortened lifespan. Moreover, HSEA-P1 and HSEA-P2 significantly protected dopaminergic neurons from α-synuclein toxicity and alleviated dopamine-associated behavioral deficits, i.e., basal slowing, ethanol avoidance, and area-restricted searching. HSEA-P1 and HSEA-P2 also up-regulated autophagy-related genes, including beclin-1/bec-1, lc-3/lgg-1, and atg-7/atg-7. RNA interference (RNAi) of these genes in transgenic α-synuclein worms confirmed that lc-3/lgg-1 and atg-7/atg-7 were required for α-synuclein degradation and DAergic neuroprotection activities of HSEA-P1 and HSEA-P2. NMR and mass spectrometry analysis revealed that the HSEA-P1 and HSEA-P2 contained diterpene glycosides.ConclusionThese findings indicate that diterpene glycosides extracted from H. scabra decreases α-synuclein accumulation and protects α-synuclein-mediated DAergic neuronal loss and its toxicities via lgg-1 and atg-7.
| S-EPMC8381228 | biostudies-literature
Project description:Estrogen has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms, as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-? (ER?) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ER? ligand-mediated neuroprotective effects in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ER? ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ER? from astrocytes, whereas conditional deletion of ER? from neurons had no significant effect. These findings show that signaling through ER? in astrocytes, but not through ER? in neurons, is essential for the beneficial effects of ER? ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiology of sex hormone effects in diverse CNS disorders.
| S-EPMC3102368 | biostudies-other
Project description:GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson's disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg-1·d-1, i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg-1·d-1, i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP+-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12α-Syn A53T) cells, treatment with GM1 ganglioside (40 μM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP+-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12α-Syn A53T cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12α-Syn A53T cells and the MPP+-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.
| S-EPMC8115090 | biostudies-literature
Project description:Regulation of VDAC by α-synuclein (αSyn) is a rich and instructive example of protein-protein interactions catalyzed by a lipid membrane surface. αSyn, a peripheral membrane protein involved in Parkinson's disease pathology, is known to bind to membranes in a transient manner. αSyn's negatively charged C-terminal domain is then available to be electromechanically trapped by the VDAC β-barrel, a process that is observed in vitro as the reversible reduction of ion flow through a single voltage-biased VDAC nanopore. Binding of αSyn to the lipid bilayer is a prerequisite of the channel-protein interaction; surprisingly, however, we find that the strength of αSyn binding to the membrane does not correlate in any simple way with its efficiency of blocking VDAC, suggesting that the lipid-dependent conformations of the membrane-bound αSyn control the interaction. Quantitative models of the free energy landscape governing the capture and release processes allow us to discriminate between several αSyn (sub-) conformations on the membrane surface. These results, combined with known structural features of αSyn on anionic lipid membranes, point to a model in which the lipid composition determines the fraction of αSyn molecules for which the charged C terminal domain is constrained to be close, but not tightly bound, to the membrane surface and thus readily captured by the VDAC nanopore. We speculate that changes in the mitochondrial membrane lipid composition may be key regulators of the αSyn-VDAC interaction and consequently of VDAC-facilitated transport of ions and metabolites in and out of mitochondria and, i.e. mitochondrial metabolism.
| S-EPMC8255272 | biostudies-literature
Project description:Many risk loci for Parkinson’s disease (PD) have been identified by genome-wide association studies (GWAS), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel SNP rs199347) to GPNMB, through colocalization analyses of expression quantitative trait locus (eQTL) and PD risk signals, confirmed by allele-specific expression studies in human brain. In cells, Glycoprotein Nonmetastatic Melanoma Protein B protein (GPNMB) co-immunoprecipitated and co-localized with alpha-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 781 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene, with potential for biomarker development and therapeutic targeting.
2022-06-17 | GSE206327 | GEO
Project description:Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of a-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Neuron-derived octopamine acts on astrocytes via a TAAR1-Orai1-Ca2+-calcineurinmediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by a-synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and hence neuroprotection with implications to a-synucleinopathies.
2023-04-01 | GSE213875 | GEO
Project description:It is well established that α-synuclein (α-syn) binding from solution to the surface of membranes composed of negatively charged and/or non-lamellar lipids can be characterized by equilibrium dissociation constants of tens of micromolar. Previously, we have found that a naturally occurring nanopore of the mitochondrial voltage-dependent anion channel (VDAC), reconstituted into planar bilayers of a plant-derived lipid, responds to α-syn at nanomolar solution concentrations. Here, using lipid mixtures that mimic the composition of mitochondrial outer membranes, we show that functionally important binding does indeed take place in the nanomolar range. We demonstrate that the voltage-dependent rate at which a membrane-embedded VDAC nanopore captures α-syn is a strong function of membrane composition. Comparison of the nanopore results with those obtained by the bilayer overtone analysis of membrane binding demonstrates a pronounced correlation between the two datasets. The stronger the binding, the larger the on-rate, but with some notable exceptions. This leads to a tentative model of α-syn-membrane interactions, which assigns different lipid-dependent roles to the N- and C-terminal domains of α-syn accounting for both electrostatic and hydrophobic effects. As a result, the rate of α-syn capture by the nanopore is not simply proportional to the α-syn concentration on the membrane surface but found to be sensitive to the specific interactions of each domain with the membrane and nanopore.
| S-EPMC6418135 | biostudies-literature
Project description:We previously demonstrated that the neuropeptide cocaine- and amphetamine-regulated transcript (CART) is protective against focal cerebral ischemia in vivo and against neuronal cell death in culture induced by oxygen-glucose deprivation (OGD). The mechanism of neuroprotection by CART is unknown, in part due to lack of knowledge regarding its putative receptor. Using a yeast two-hybrid system with CART's carboxy-terminal to screen a mouse brain cDNA library, we uncovered a potential direct interaction between CART and subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB). We confirmed CART/SDHB binding using in vitro pull-down assay, and tested the effects of CART peptide on SDH activity, Complex II (CII) activity and ATP production in primary cultured cortical neurons under basal conditions and after OGD. At concentrations between 0.2 and 4 nM, CART significantly increased SDH function, CII activity and ATP generation in purified mitochondria and intact neurons under baseline conditions. Furthermore, pretreatment with CART enhanced mitochondrial mechanisms of neuronal survival and prevented the decline in SDH and CII activities and ATP production after OGD. The findings suggest that CART's neuroprotective mechanism of action may be linked to preservation of mitochondrial function and prevention of energy failure after ischemia-reperfusion injury.
| S-EPMC2582219 | biostudies-literature
Project description:Misfolding and oligomerization of unstructured proteins is involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease, Huntington's disease, and other neurodegenerative disorders. Elucidation of possible conformations of these proteins and their interactions with the membrane is necessary to understand the molecular mechanisms of neurodegeneration. We developed a strategy that makes it possible to elucidate the molecular mechanisms of alpha-synuclein aggregation-a key molecular event in the pathogenesis of PD. This strategy can be also useful for the study of other unstructured proteins involved in neurodegeneration. The results of these theoretical studies have been confirmed with biochemical and electrophysiological studies. Our studies provide insights into the molecular mechanism for PD initiation and progression, and provide a useful paradigm for identifying possible therapeutic interventions through computational modeling.
| S-EPMC2627560 | biostudies-literature