Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction

Morales‐Briceño, Hugo; Ha, Ainhi D.; London, Kerry; Farlow, David; Chang, Florence; Fung, Victor S.C.

doi:10.1016/j.parkreldis.2019.04.004

Cited by 27 publications

(37 citation statements)

References 13 publications

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“…X-linked recessive mutations in PGK1 cause enzymatic deficiency through haploinsufficiency and have been linked with levodopa-responsive parkinsonism and nigrostriatal denervation, thus providing an association between decreased glycolysis and PD in humans. 4 Moreover, PGK1 is in the Xq21-q25 location of the PARK12 susceptibility locus as reported in three different PD-linkage studies. 5 The limitations of the study by Cai and colleagues 2 are inherent to the shortcomings of animal models to recapitulate human PD pathology and the retrospective analysis of datasets with small number of patients treated with TZ.…”

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confidence: 74%

“…The study by Cai and colleagues provides evidence that TZ has potential disease‐modifying effects in several PD models through the enhancement of glycolysis. X‐linked recessive mutations in PGK1 cause enzymatic deficiency through haploinsufficiency and have been linked with levodopa‐responsive parkinsonism and nigrostriatal denervation, thus providing an association between decreased glycolysis and PD in humans . Moreover, PGK1 is in the Xq21‐q25 location of the PARK12 susceptibility locus as reported in three different PD‐linkage studies .…”

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confidence: 83%

“…Terazosin (TZ) is an α1‐adrenergic receptor antagonist licensed for the treatment of prostatism that has been shown to increase cell phosphoglycerate kinase (PGK1) activity . The glycolytic pathway is composed of 10 different enzymatic reactions, and PGK1 is the first that directly leads to the generation of adenosine triphosphate (ATP) …”

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confidence: 99%

“…3 The glycolytic pathway is composed of 10 different enzymatic reactions, and PGK1 is the first that directly leads to the generation of adenosine triphosphate (ATP). 4 In a series of experiments, they first administered TZ to normal mice and observed an increase of ATP levels in the substantia nigra pars compacta (SNc), striatum, and cortex. Subsequently, they demonstrated that the administration of TZ ameliorated SNc and striatum neuronal loss and improved motor performance in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model.…”

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confidence: 99%

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Enhancement of glycolysis: A Potential Disease‐Modifying Strategy for Parkinson's Disease

Morales‐Briceño

Fung

2019

Movement Disorders

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confidence: 74%

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confidence: 83%

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confidence: 99%

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confidence: 99%

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Enhancement of glycolysis: A Potential Disease‐Modifying Strategy for Parkinson's Disease

Morales‐Briceño

Fung

2019

Movement Disorders

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“…PGK1 serves a speed limiting role in the second stage of glycolysis during the regulation of energy production and redox balance ( 27 ). Aberrant PGK1 expression has been previously associated with the occurrence of a number of diseases, including Parkinson's disease and hereditary non-spherical hemolytic anemia ( 28 - 30 ). By contrast, the PGK2 gene is only expressed in spermatogenic cells, where its only known function is to compensate for the inhibition of PGK1 expression caused by the inactivation of X chromosomes in spermatocytes ( 31 ).…”

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confidence: 99%

Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell‑like properties and the epithelial‑mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway

et al. 2020

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Although it has been previously documented that a hypoxic environment can promote glycolysis and the malignant progression of oral squamous cell carcinoma (OSCC) cells, the specific underlying mechanism remains unclear. Phosphoglycerate kinase 1 (PGK1) has been previously reported to serve an important role in tumor metabolism. The aim of the present study was to investigate the effects of hypoxia and PGK1 on glycolysis, stem cell-like properties and epithelial-mesenchymal transition (EMT) in OSCC cells. Cell Counting Kit-8 assays were performed to examine tumor cell viability under hypoxic conditions. Sphere formation, immunohistochemistry, western blotting, Transwell assays and mouse xenograft studies were performed to assess the biological effects of PGK1. Under hypoxic conditions, phosphoglycerate PGK1 expression was found to be upregulated, which resulted in the potentiation of stem cell-like properties and enhancement of EMT. However, PGK1 knockdown reversed hypoxia-mediated glycolysis, stem cell-like properties, EMT in addition to inhibiting OSCC cell invasion and migration. PGK1 knockdown also inhibited tumour growth, whilst the overexpression of PGK1 was demonstrated to promote tumour growth in mouse xenograft models in vivo . Downstream, activation of the AKT signalling pathway reversed the series of changes induced by PGK1 knockdown. PGK1 expression was found to be upregulated in human OSCC tissues, which was associated with the pathological differentiation of tumours and lymph node metastasis. To conclude, results from the present study demonstrate that hypoxia can increase PGK1 expression, resulting in the promotion of glycolysis, enhancing stem cell-like properties and EMT by activating AKT signalling in OSCC.

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Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review

Scheibler

Eeghen

Koning

et al. 2022

Movement Disord Clin Pract

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Background With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results The literature search yielded 208 reports for data‐extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta‐propeller protein‐associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic‐lysosomal and ubiquitin‐proteasome system. Conclusion Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.

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Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction

Cited by 27 publications

References 13 publications

Enhancement of glycolysis: A Potential Disease‐Modifying Strategy for Parkinson's Disease

Enhancement of glycolysis: A Potential Disease‐Modifying Strategy for Parkinson's Disease

Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell‑like properties and the epithelial‑mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review

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