Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases

Zhang, Xiaoyan; Lee, Weithye; Bian, Jun

doi:10.3390/cells11244075

Cited by 19 publications

(6 citation statements)

References 122 publications

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“…31 Other proteins found in plasma EVs and expressed in neurons are neuro lament medium and light chains and ATPase Na+/K + transporting subunit α 3 (ATP1A3), an enzyme involved in the action potential propagation during neuronal depolarization. 32 Not only neuronal, but also glial proteins, like GFAP, 33 EAAT2, glutamine synthetase (GLNA), and the major CNS myelin protein, proteolipid protein 1 (PLP1) were detected in plasma EVs. Moreover, we identi ed mitochondrial proteins involved in the tra c of various solutes across the inner mitochondrial membrane (SLC25A4 and SLC25A6), glucose metabolism (HXK1) and oxidative phosphorylation (ATP5F1A and NDUFS1).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profile of Extracellular Vesicles from Plasma and CFS of Multiple Sclerosis Patients Reveals Disease Activity- Associated EAAT2

D’Ambrosio,

Zamboni,

Camerini

et al. 2024

Preprint

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Background and Objectives There is an urgent need to discover blood-based biomarkers of multiple sclerosis (MS) to better define the underlying biology of relapses and monitor disease progression. The main goal of this study is to search for candidate biomarkers of MS relapses associated with circulating extracellular vesicles (EVs), an emerging tool for biomarker discovery. Methods EVs, purified from unpaired plasma and CSF samples of RRMS patients by size-exclusion chromatography (SEC), underwent qualitative proteomic analysis to discover novel biomarkers associated with MS relapses. The candidate biomarkers of disease activity were detected by comparison approach between plasma- and CSF-EV proteomes associated with relapses. Among them, a selected potential biomarker was evaluated in a cohort of MS patients, using a novel and highly reproducible flow cytometry-based approach in order to detect low abundant EV subsets in a complex body fluid such as plasma. Results The proteomic profiles of both SEC-purified plasma EVs (from 6 patients in relapse and 5 patients in remission) and SEC-puirified CSF EVs (from 4 patients in relapse and 3 patients in remission) revealed a set of proteins associated with MS relapses significant enriched in the synaptic transmission pathway. Among common proteins, excitatory amino-acid transporter 2, EAAT2, responsible for the majority of the glutamate uptake in CNS, was worthy of further investigation. By screening plasma samples from 110 MS patients, we found a significant association of plasma EV-carried EAAT2 protein (EV-EAAT2) with MS relapses, regardless of disease-modifying therapies. This finding was confirmed by investigating the presence of EV-EAAT2 in plasma samples collected longitudinally from 10 RRMS patients, during relapse and remission. Moreover, plasma EV-EAAT2 levels correlated positively with Expanded Disability Status Scale (EDSS) score in remitting MS patients but showed a negative correlation in patients with secondary progressive (SPMS) and EDSS > 3. Conclusion Our results emphaticize the usefulness of plasma EVs as a source of accessible biomarkers to remotely analyse the CNS status. Plasma EV-EAAT2 showed to be a promising biomarker for MS relapses. Further studies are required to assess the clinical relevance of this biomarker also for disability progression independent of relapse activity and transition from RRMS towards SPMS.

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Section: Discussionmentioning

confidence: 99%

Proteomic Profile of Extracellular Vesicles from Plasma and CFS of Multiple Sclerosis Patients Reveals Disease Activity- Associated EAAT2

D’Ambrosio,

Zamboni,

Camerini

et al. 2024

Preprint

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“…Importantly, our observations indicate that PD neurons have a more depolarized membrane potential when compared to HD neurons, which may be attributed to the lower expression of Na+/K+-ATPase 23 . Notably, mutations in this complex have been also associated with early onset of PD [24][25][26] . Interestingly, α-synuclein has been shown to block and disrupt the function of Na + /K + -ATPase, resulting in an increase in the intracellular Na + concentration what may lead to attenuation of Ca 2+ extrusion via the Na + /Ca 2+ exchanger and neuronal cell death 27,28 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial fitness influences neuronal excitability of dopaminergic neurons from patients with idiopathic form of Parkinson’s disease

Chlebanowska

Szlaga

Tejchman-Skrzyszewska

et al. 2023

Preprint

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Parkinson disease is the second most common neurodegenerative disease defined by presence of Lewy bodies and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). There are three types of PD - familial, early-onset and idiopathic. Idiopathic PD (IPD) accounts for approximately 90% of all PD cases. Mitochondrial dysfunction accompanies the pathogenesis of Parkinson's disease. Loss of mitochondrial function increases oxidative stress and calcium buffering, which in turn hinders the production of ATP and disrupts the functioning of dopaminergic neurons. The main barrier in PD research was the lack of proper human models to study the mechanisms of PD development and progression. Using induced pluripotent stem (iPS) cells we generated patient-specific dopaminergic neurons. We observed differences in the mitochondria fitness but not differences in mitochondria mass, morphology or membrane potential. Expression of OXPHOS mitochondrial complexes were lower in PD patients in comparison to control group what resulted in changes in mitochondria respiratory status. We observed also lower expression levels of Na+/K+-ATPase subunits and ATP-sensitive K+ (K-ATP) channel subunits. The lower oxygen consumption rate and extracellular acidification rate values were observed in dopaminergic progenitors and iPSC from PD patients compared to the control group. Importantly, observed decrease in the availability of ATP and in the energy consumption, as well as changes in acidification, may constitute contributing factors to the observed reduced neuronal excitability of PD patients dopaminergic neurons.

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“…Previous studies have demonstrated that the attenuation of Na + /K + -ATPase activity may be due to the direct interaction of xenobiotic compounds with the enzyme [ 44 ] and also due to the raised lipid peroxidation which, in turn, impairs the structure of Na + /K + -ATPase [ 45 , 46 , 47 ]. In previous studies, single CPF or GLY treatment could initiate or exacerbate the generation of reactive oxygen species (ROS) and oxidative stress and then causes oxidative damage in fish [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective

Zhang,

Ding,

Liu

et al. 2023

IJMS

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Chlorpyrifos (CPF) and glyphosate (GLY) are the most widely used organophosphate insecticide and herbicide worldwide, respectively; co-occurrence of CPF and GLY in aquatic environments occurs where they inevitably have potential hazards to fish. However, the potential mechanisms of CPF and GLY to induce toxicity have not been fully explored. To identify the adverse impacts of CPF and GLY on fish, either alone or in combination (MIX), CPF (25 μg/L) and GLY (3.5 mg/L) were set up according to an environmentally relevant concentration to expose to common carp for 21 days. After exposure, CPF and GLY decreased the activities of acetylcholinesterase and Na+/K+-ATPase, altered monoamine oxidase levels, decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase and glutamic reductase), and induced the accumulation of malondialdehyde in the carp brain. The parameters in the MIX groups had a greater impact compared to that in the CPF or GLY group, suggesting that both single and combined exposure could affect neurological signaling systems and cause oxidative stress and lipid peroxidation damage in carp brains, and that MIX exposure increases the impact of each pollutant. RNA-seq results showed that single or combined exposure to CPF and GLY induced global transcriptomic changes in fish brains, and the number of differentially expressed genes in MIX-treated carp brains were globally increased compared to either the CPF or GLY groups, suggesting that the effects of co-exposure were greater than single exposure. Further analysis results revealed that the global transcriptomic changes participated in oxidative stress, immune dysfunction, and apoptosis of fish brains, and identified that the P13k-Akt signaling pathway participates in both single and combined exposure of CPF- and GLY-induced toxicity. Taken together, our results demonstrated that the interaction of CPF and GLY might be synergic and provided novel insights into the molecular mechanisms of fish brains coping with CPF and GLY.

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Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases

Cited by 19 publications

References 122 publications

Proteomic Profile of Extracellular Vesicles from Plasma and CFS of Multiple Sclerosis Patients Reveals Disease Activity- Associated EAAT2

Proteomic Profile of Extracellular Vesicles from Plasma and CFS of Multiple Sclerosis Patients Reveals Disease Activity- Associated EAAT2

Mitochondrial fitness influences neuronal excitability of dopaminergic neurons from patients with idiopathic form of Parkinson’s disease

Single and Combined Effects of Chlorpyrifos and Glyphosate on the Brain of Common Carp: Based on Biochemical and Molecular Perspective

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