Exploring glycolytic enzymes in disease: potential biomarkers and therapeutic targets in neurodegeneration, cancer and parasitic infections DOI Creative Commons
Maura Rojas-Pirela, Diego Andrade-Alviárez, Verónica Rojas

et al.

Open Biology, Journal Year: 2025, Volume and Issue: 15(2)

Published: Feb. 1, 2025

Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it responsible for generating ATP cell through conversion glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed electron chain mitochondria to produce additional by oxidative phosphorylation), as well producing intermediates that can serve substrates other processes. Glycolysis takes place 10 consecutive chemical reactions, each which catalysed specific enzyme. Although energy transduction metabolism main function this pathway, involvement virulence, growth, pathogen–host interactions, immunomodulation adaptation environmental conditions are functions attributed pathway. In humans, where glycolysis occurs mainly cytosol, mislocalization some glycolytic enzymes various subcellular locations, alterations their expression regulation, been associated with development progression diseases. review, we describe role pathogenesis diseases clinical interest. addition, potential these targets drug use diagnostic prognostic markers pathologies also discussed.

Language: Английский

The role of microRNA-34 family in Alzheimer’s disease: A potential molecular link between neurodegeneration and metabolic disorders DOI
Maryam Bazrgar, Pariya Khodabakhsh, Mercedes Prudencio

et al.

Pharmacological Research, Journal Year: 2021, Volume and Issue: 172, P. 105805 - 105805

Published: Aug. 8, 2021

Language: Английский

Citations

34
Vitamin B12 impacts amyloid beta-induced proteotoxicity by regulating the methionine/S-adenosylmethionine cycle DOI Creative Commons

Andy B. Lam,

Kirsten Kervin,

Jessica E. Tanis

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 36(13), P. 109753 - 109753

Published: Sept. 1, 2021

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as modifiable risk factor for AD, could potentially be targeted to slow onset and progression. However, complexity of the human diet indirect effects microbiome make it challenging identify protective nutrients. Multiple factors contribute AD pathogenesis, including amyloid beta (Aβ) deposition, energy crisis, oxidative stress. Here, we use Caenorhabditis elegans define impact on Aβ proteotoxicity. We discover that dietary vitamin B

Language: Английский

Citations

34
Monitoring and modelling the dynamics of the cellular glycolysis pathway: A review and future perspectives DOI Creative Commons
Nitin Patil, Orla Howe, Paul A. Cahill

et al.

Molecular Metabolism, Journal Year: 2022, Volume and Issue: 66, P. 101635 - 101635

Published: Nov. 12, 2022

The dynamics of the cellular glycolysis pathway underpin function and dysfunction, therefore ultimately health, disease, diagnostic therapeutic strategies. Evolving our understanding this fundamental process its remains critical.

Language: Английский

Citations

27
Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease DOI Creative Commons
Xin Zhang, Long Wu, Russell H. Swerdlow

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(3), P. 410 - 410

Published: Jan. 25, 2023

Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer's disease (LOAD), whereas ApoE2 reduces LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized knock-in mouse models to investigate relationships among isoforms, glycolytic metabolism, health aging. ApoE2-expressing retained robust hexokinase (HK) expression activity, these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE4 glycolysis directly correlated markers of cellular wellness. Moreover, upregulated phosphofructokinase pyruvate kinase apparent intent compensating HK-dependent reduction. introduction increased HK levels flux PI3K/Akt signaling was distinctively regulated by only partially responsible ApoE-mediated HK. Collectively, our findings indicate differentially modulate through regulation, upregulating downregulating, which markedly impacts during lend compelling support emerging inverse-Warburg theory AD highlight a therapeutic opportunity bolstering resilience prevent treat AD.

Language: Английский

Citations

15
Glymphatic System and Mitochondrial Dysfunction as Two Crucial Players in Pathophysiology of Neurodegenerative Disorders DOI Open Access

Kamila Kopeć,

Stanisław Szleszkowski,

Dariusz Koziorowski

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(12), P. 10366 - 10366

Published: June 20, 2023

Neurodegenerative diseases are a complex problem affecting millions of people around the world. The pathogenesis is not fully understood, but it known that both insufficiency glymphatic system and mitochondrial disorders affect development pathology. It appears these just two independent factors coexist in processes neurodegeneration, they often interact drive each other. Bioenergetics disturbances potentially associated with accumulation protein aggregates impaired clearance. Furthermore, sleep characteristic neurodegeneration may impair work activity mitochondria. Melatonin be one elements linking function systems. Moreover, noteworthy this context process neuroinflammation inextricably linked to mitochondria its impact only on neurons, also glia cells involved This review presents possible direct indirect connections between neurodegeneration. Clarifying connection areas relation could lead new multidirectional therapies, which, due complexity pathogenesis, seems worth considering.

Language: Английский

Citations

15
Lower GLUT1 and unchanged MCT1 in Alzheimer’s disease cerebrovasculature DOI Creative Commons

Manon Leclerc,

Cyntia Tremblay,

Philippe Bourassa

et al.

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2024, Volume and Issue: 44(8), P. 1417 - 1432

Published: March 5, 2024

The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates (MCT1) respectively transport across the blood-brain barrier. While reduced uptake by one earliest signs Alzheimer’s disease (AD), no change in has been evidenced yet. To probe for changes GLUT1 MCT1, we performed Western immunoblotting microvessel extracts from parietal cortex 60 participants Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels GLUT1, whereas MCT1 remained unchanged. reduction was associated cognitive scores. No such association found MCT1. inversely correlated neuritic plaques β-secretase-derived fragment levels. other significant associations were between both transporters, markers Aβ tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while deficit may underlie to AD, impairment occurs This study thus supports exploration an alternative energy source aging brain.

Language: Английский

Citations

6
Dopamine modification of glycolytic enzymes impairs glycolysis: possible implications for Parkinson’s disease DOI Creative Commons
Bing Chen, Qian Zhang,

Xiaoru Zhong

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 29, 2024

Abstract Background Parkinson’s disease (PD), a chronic and severe neurodegenerative disease, is pathologically characterized by the selective loss of nigrostriatal dopaminergic neurons. Dopamine (DA), neurotransmitter produced neurons, its metabolites can covalently modify proteins, dysregulation this process has been implicated in neuronal PD. However, much remains unknown about protein targets. Methods In present work, we designed synthesized dopamine probe (DA-P) to screen identify potential targets DA using activity-based profiling (ABPP) technology combination with liquid chromatography-tandem mass spectrometry (LC–MS/MS). situ pull-down assays, cellular thermal shift assays (CETSAs) immunofluorescence were performed confirm modifications on these hits. To investigate effects modifications, measured enzymatic activities target evaluated glycolytic stress mitochondrial respiration Seahorse tests, systematically analyzed changes unbiased LC–MS/MS-based non-targeted metabolomics profiling. Results We successfully identified three aldolase A, α-enolase pyruvate kinase M2 (PKM2), as binding partners DA. bound Glu166 α-enolase, Cys49 Cys424 PKM2, Lys230 inhibiting PKM2 thereby impairing ATP synthesis, resulting dysfunction. Conclusions Recent research revealed that enhancing glycolysis offer protection against The study pathway vulnerable disruption DA, suggesting promising avenue for therapeutic interventions. Safeguarding DA-related could be intervention

Language: Английский

Citations

5
l-Lactate: Food for Thoughts, Memory and Behavior DOI Creative Commons
María Fernanda Veloz Castillo, Pierre J. Magistretti, Corrado Calì

et al.

Metabolites, Journal Year: 2021, Volume and Issue: 11(8), P. 548 - 548

Published: Aug. 20, 2021

More and more evidence shows how brain energy metabolism is the linkage between physiological morphological synaptic plasticity memory consolidation. Different types of are associated with differential inputs, each specific inputs that upstream diverse molecular cascades depending on receptor activity. No matter heterogeneous response is, availability represents lowest common denominator since all these mechanisms consuming networks adapt their performance accordingly. Astrocytes exert a primary role in this sense by acting as an buffer; glycogen granules, mechanism to store glucose, redistributed at glance conveyed neurons via Astrocyte–Neuron Lactate Shuttle (ANLS). Here, we review different relate delivery brain.

Language: Английский

Citations

31
Optimized sample preparation and data analysis for TMT proteomic analysis of cerebrospinal fluid applied to the identification of Alzheimer’s disease biomarkers DOI Creative Commons
Sophia Weiner,

Mathias Sauer,

Pieter Jelle Visser

et al.

Clinical Proteomics, Journal Year: 2022, Volume and Issue: 19(1)

Published: May 14, 2022

Abstract Background Cerebrospinal fluid (CSF) is an important biofluid for biomarkers of neurodegenerative diseases such as Alzheimer’s disease (AD). By employing tandem mass tag (TMT) proteomics, thousands proteins can be quantified simultaneously in large cohorts, making it a powerful tool biomarker discovery. However, TMT proteomics CSF associated with analytical challenges regarding sample preparation and data processing. In this study we address those ranging from normalization over to analysis. Method Using liquid chromatography coupled mass-spectrometry (LC–MS), analyzed multiplex samples consisting either identical or individual samples, evaluated quantification accuracy tested the performance different approaches. We examined MS2 MS3 acquisition strategies performed comparative evaluation filter-assisted (FASP) in-solution protocol. Finally, four approaches (median, quantile, Total Peptide Amount, TAMPOR) were applied previously published European Medical Information Framework Disease Multimodal Biomarker Discovery (EMIF-AD MBD) dataset. Results The correlation measured reporter ratios spiked-in standard peptide amounts was significantly lower multiplexes composed compared aliquots single pool, demonstrating that heterogeneous composition influences quantitation. Comparison methods showed could improved by applying median- quantile-based normalization. slope acquiring mode, albeit at expense 29% decrease number identified proteins. FASP 73% overlap using optimized normalization, present list 64 candidates (clinical AD vs. controls, p < 0.01) EMIF-AD cohort. Conclusion have several aspects CSF. results our provide practical guidelines improve aid design extracted cohort valuable basis future studies help elucidate pathogenic mechanisms AD.

Language: Английский

Citations

22
The unique neuropathological vulnerability of the human brain to aging DOI Creative Commons
Isidró Ferrer

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 87, P. 101916 - 101916

Published: March 28, 2023

Alzheimer's disease (AD)-related neurofibrillary tangles (NFT), argyrophilic grain (AGD), aging-related tau astrogliopathy (ARTAG), limbic predominant TDP-43 proteinopathy (LATE), and amygdala-predominant Lewy body (LBD) are proteinopathies that, together with hippocampal sclerosis, progressively appear in the elderly affecting from 50% to 99% of individuals aged 80 years, depending on disease. These disorders usually converge same subject associate additive cognitive impairment. Abnormal Tau, TDP-43, α-synuclein pathologies progress following a pattern consistent an active cell-to-cell transmission abnormal protein processing host cell. However, cell vulnerability pathways specific for each disorder, albeit proteins may co-localize particular neurons. All these alterations unique or highly prevalent humans. They all affect, at first, archicortex paleocortex extend later stages neocortex other regions telencephalon. observations show that phylogenetically oldest areas human cerebral cortex amygdala not designed cope lifespan actual New strategies aimed reducing functional overload telencephalon, including optimization dream repair mechanisms implementation artificial circuit devices surrogate brain functions, promising.

Language: Английский

Citations

11