Glycolysis: The Next Big Breakthrough in Parkinson’s Disease

Naeem, Unaiza; Arshad, Abdul Rehman; Jawed, Areesha; Eqbal, Farea; Imran, Laiba; Khan, Zayeema; Ijaz, Farhat

doi:10.1007/s12640-022-00579-3

Cited by 7 publications

(5 citation statements)

References 84 publications

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“…The mammalian brain depends mostly on glucose as a source of energy [ 44 ]. Changes in glycolysis are observed in several neurodegenerative diseases [ 21 , 43 , 45 ]. Indeed, phosphoglycerate kinase 1 (PGK-1), the first ATP-producing enzyme in glycolysis, has been linked to PD [ 46 ], as its deficiency was generally found in male PD patients [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

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Dopamine modification of glycolytic enzymes impairs glycolysis: possible implications for Parkinson’s disease

Chen,

Zhang,

Zhong

et al. 2024

Cell Commun Signal

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

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Section: Discussionmentioning

confidence: 99%

“…Moreover, glycolytic deficits have also been reported to be associated with PD [ 20 ]. As enhancing glycolysis is neuroprotective in PD [ 21 ], our findings potentially suggest that preventing the modification of glycolytic enzymes by DA could be an alternative treatment strategy for PD.…”

Section: Introductionmentioning

confidence: 99%

Dopamine modification of glycolytic enzymes impairs glycolysis: possible implications for Parkinson’s disease

Chen,

Zhang,

Zhong

et al. 2024

Cell Commun Signal

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“…Therefore, brain energy demand is mostly met by the metabolism of glucose [ 162 ]. Bioenergetic and mitochondrial dysfunction are common hallmarks of PD and ALS, and regulate disease onset and progression [ 161 , 163 , 164 ]. In ALS pathogenesis, the early dysregulation of the AMPK signaling pathway was found in motor neurons and in a large proportion of patients [ 165 ].…”

Section: α 1 -Ar Antagonistsmentioning

confidence: 99%

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

Perez

2023

IJMS

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α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

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“… 15 Terazosin, an α 1‐adrenergic receptor antagonist, has demonstrated efficacy in augmenting glycolysis by activating an initial ATP‐producing enzyme in the glycolytic pathway, thereby increasing intracellular ATP levels, 16 and exhibiting potential therapeutic effects in diseases such as Parkinson. 17 , 18 , 19 Increasing ATP could play a role in retarding cellular ageing, 20 as well as enhancing the activity of endothelial nitric oxide synthase to facilitate the release of nitric oxide and vasodilation. 21 , 22 Considering the association between vascular stiffness and metabolic inflexibility, similar to the ageing process, 23 we hypothesised that Terazosin may also have efficacy on anti‐vascular stiffness.…”

Section: Introductionmentioning

confidence: 99%

“…These cells regulate membrane transport and barrier function through their proper metabolic processes, particularly energy metabolism 15 . Terazosin, an α 1‐adrenergic receptor antagonist, has demonstrated efficacy in augmenting glycolysis by activating an initial ATP‐producing enzyme in the glycolytic pathway, thereby increasing intracellular ATP levels, 16 and exhibiting potential therapeutic effects in diseases such as Parkinson 17–19 . Increasing ATP could play a role in retarding cellular ageing, 20 as well as enhancing the activity of endothelial nitric oxide synthase to facilitate the release of nitric oxide and vasodilation 21,22 .…”

Section: Introductionmentioning

confidence: 99%

Effect of low‐dose terazosin on arterial stiffness improvement: A pilot study

Guan,

Zhang,

Chen

et al. 2024

J Cellular Molecular Medi

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Arterial stiffness, a prominent hallmark of ageing arteries, is a predictor of all‐cause mortality. Strategies for promoting healthy vascular ageing are encouraged. Here we conducted a pilot study to evaluate the potential effects of low‐dose Terazosin on arterial stiffness. We enrolled patients aged over 40 with elevated arterial stiffness, defined as a brachial‐ankle pulse wave velocity (baPWV) ≥1400 cm/s, who were administered Terazosin (0.5 and 1.0 mg/day) from December 2020 to June 2023. Treatment responses were assessed every 3 months. Linear regression analysis was used to characterise the improvement. We matched cases who took Terazosin for 1 year with Terazosin‐free controls using propensity score matching (PSM). Our findings demonstrate that Terazosin administration significantly affected arterial stiffness. (1) Arterial stiffness significantly improved (at least a 5% reduction in baPWV) in 50.0% of patients at 3 months, 48.6% at 6 months, 59.3% at 9 months, and 54.4% at 12 months, respectively. (2) Those with higher baseline baPWV and hypertension exhibited a significantly reduced risk of non‐response. (3) Terazosin was associated with a reduction of baPWV at 1‐year follow‐up (linear regression: β = −165.16, p < 0.001). This pilot study offers valuable insights into the potential significance of Terazosin in improving arterial stiffness and paves the way for future randomised clinical trials in combating vascular ageing.

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Glycolysis: The Next Big Breakthrough in Parkinson’s Disease

Cited by 7 publications

References 84 publications

Dopamine modification of glycolytic enzymes impairs glycolysis: possible implications for Parkinson’s disease

Dopamine modification of glycolytic enzymes impairs glycolysis: possible implications for Parkinson’s disease

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

Effect of low‐dose terazosin on arterial stiffness improvement: A pilot study

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