Analysis of circulating metabolites to differentiate Parkinson’s disease and essential tremor

Ostrakhovitch, Elena A.; Song, Eun-Suk; Macêdo, Jéssica K. A.; Gentry, Matthew S.; Quintero, Jorge E.; Horne, Craig van; Yamasaki, Tritia R.

doi:10.1016/j.neulet.2021.136428

Cited by 6 publications

(4 citation statements)

References 42 publications

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“…We observed a 3-fold lower GSH/GSSG ratio for PM as compared to SM floor plate cells. Very similar observations have been reported for day 25 PRKN-KO hiPSC-derived mesencephalic dopamine neurons 111 , as well as for PD patient tissue 112 . The absence of functional parkin causes abnormal mitochondrial morphology and function resulting in increased oxidative stress 36 , 113 .…”

Section: Discussionsupporting

confidence: 86%

Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions

Cukier

Kim

Griswold

et al. 2022

npj Parkinsons Dis.

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We previously reported on two brothers who carry identical compound heterozygous PRKN mutations yet present with significantly different Parkinson’s Disease (PD) clinical phenotypes. Juvenile cases demonstrate that PD is not necessarily an aging-associated disease. Indeed, evidence for a developmental component to PD pathogenesis is accumulating. Thus, we hypothesized that the presence of additional genetic modifiers, including genetic loci relevant to mesencephalic dopamine neuron development, could potentially contribute to the different clinical manifestations of the two brothers. We differentiated human-induced pluripotent stem cells (hiPSCs) derived from the two brothers into mesencephalic neural precursor cells and early postmitotic dopaminergic neurons and performed wholeexome sequencing and transcriptomic and metabolomic analyses. No significant differences in the expression of canonical dopamine neuron differentiation markers were observed. Yet our transcriptomic analysis revealed a significant downregulation of the expression of three neurodevelopmentally relevant cell adhesion molecules, CNTN6, CNTN4 and CHL1, in the cultures of the more severely affected brother. In addition, several HLA genes, known to play a role in neurodevelopment, were differentially regulated. The expression of EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further identified differences in cellular processes relevant to dopamine metabolism. Lastly, wholeexome sequencing, transcriptomics and metabolomics data all revealed differences in glutathione (GSH) homeostasis, the dysregulation of which has been previously associated with PD. In summary, we identified genetic differences which could potentially, at least partially, contribute to the discordant clinical PD presentation of the two brothers.

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Section: Discussionsupporting

confidence: 86%

Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions

Cukier

Kim

Griswold

et al. 2022

npj Parkinsons Dis.

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“…Nicotinamide and trehalose are neuroprotective molecules. In PD, disruption of energy homeostasis leads to dysregulation of nicotinamide production and promotes neurodegeneration 51 . A recent clinical trial of PD with nicotinamide supplementation reported a significant improvement in pathological indicators including inflammation 52 .…”

Section: Functional Inferencementioning

confidence: 99%

Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms

et al. 2022

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Parkinson’s disease (PD) may start in the gut and spread to the brain. To investigate the role of gut microbiome, we conducted a large-scale study, at high taxonomic resolution, using uniform standardized methods from start to end. We enrolled 490 PD and 234 control individuals, conducted deep shotgun sequencing of fecal DNA, followed by metagenome-wide association studies requiring significance by two methods (ANCOM-BC and MaAsLin2) to declare disease association, network analysis to identify polymicrobial clusters, and functional profiling. Here we show that over 30% of species, genes and pathways tested have altered abundances in PD, depicting a widespread dysbiosis. PD-associated species form polymicrobial clusters that grow or shrink together, and some compete. PD microbiome is disease permissive, evidenced by overabundance of pathogens and immunogenic components, dysregulated neuroactive signaling, preponderance of molecules that induce alpha-synuclein pathology, and over-production of toxicants; with the reduction in anti-inflammatory and neuroprotective factors limiting the capacity to recover. We validate, in human PD, findings that were observed in experimental models; reconcile and resolve human PD microbiome literature; and provide a broad foundation with a wealth of concrete testable hypotheses to discern the role of the gut microbiome in PD.

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“…Activation of the kynurenine pathway was also confirmed by increased plasma NADH levels in PD patients relative to healthy control. Interestingly, it was associated with increased nicotinamide phosphoribosyl transferase (that converted nicotinamide to nicotinamide mononucleotide) in PD plasma [ 160 ]. Nevertheless, levels of nicotinamide metabolites have not been studied yet in PD.…”

Section: Parkinson’s Diseasementioning

confidence: 99%

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

et al. 2023

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The prevalence of neurodegenerative diseases (NDs) is increasing due to the aging population and improved longevity. They are characterized by a range of pathological hallmarks, including protein aggregation, mitochondrial dysfunction, and oxidative stress. The aim of this review is to summarize the alterations in brain energy and amino acid metabolism in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Based on our findings, we proposed a group of selected metabolites related to disturbed energy or mitochondrial metabolism as potential indicators or predictors of disease. We also discussed the hidden challenges of metabolomics studies in NDs and proposed future directions in this field. We concluded that biochemical parameters of brain energy metabolism disruption (obtained with metabolomics) may have potential application as a diagnostic tool for the diagnosis, prediction, and monitoring of the effectiveness of therapies for NDs. However, more studies are needed to determine the sensitivity of the proposed candidates. We suggested that the most valuable biomarkers for NDs studies could be groups of metabolites combined with other neuroimaging or molecular techniques. To attain clinically applicable results, the integration of metabolomics with other “omic” techniques might be required.

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Analysis of circulating metabolites to differentiate Parkinson’s disease and essential tremor

Cited by 6 publications

References 42 publications

Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions

Genomic, transcriptomic, and metabolomic profiles of hiPSC-derived dopamine neurons from clinically discordant brothers with identical PRKN deletions

Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

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