Glycolysis and Neuroprotection in Parkinson's Disease

Parkinson’s disease is characterised by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor and non-motor symptoms. A growing body of research indicates that deficits in cellular energy metabolism, particularly in glycolytic flux, contribute to neuronal vulnerability. Glycolysis is the cytosolic pathway that converts glucose to pyruvate, yielding ATP and intermediates for biosynthetic processes. Enhancing glycolytic throughput can bolster ATP production, offset mitochondrial dysfunction and reduce oxidative stress, thereby promoting neuronal survival. Interventions targeting key enzymes, such as phosphoglycerate kinase 1, have demonstrated neuroprotective actions in cellular and animal models. Moreover, small-molecule modulators that stabilise glycolytic enzyme conformations or relieve rate-limiting steps have been shown to preserve mitochondrial integrity, prevent apoptotic cascades and maintain neurite networks. By restoring energy homeostasis, glycolysis-centred strategies hold promise for slowing disease progression and ameliorating cognitive and motor impairments.

Research from Nature Portfolio

Recent experimental work has elucidated how dual inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3α/β can exert protective effects via enhancement of glycolytic respiration. In human iPSC-derived cortical and midbrain neurons exposed to mitochondrial toxins, treatment with a specific kinase inhibitor increased the complexity of the mitochondrial network and prevented the loss of key mitochondrial markers. This agent also stimulated glycolytic ATP generation, lowered reactive oxygen species production and conferred anti-apoptotic protection. These findings underscore the interdependence of glycolytic flux and mitochondrial function in neuronal resilience and point to kinase modulation as a viable therapeutic approach for Parkinson’s disease.

Glycolysis and Neuroprotection in Parkinson's Disease publication trend

The graph below shows the total number of articles in glycolysis and neuroprotection in parkinson's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Glycolysis: The metabolic pathway converting glucose to pyruvate, generating ATP and reducing equivalents in the cytosol.

Phosphoglycerate kinase 1 (PGK1): A key glycolytic enzyme that catalyses the transfer of a phosphate from 1,3-bisphosphoglycerate to ADP, yielding ATP.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage cellular components and contribute to neurodegeneration.

Mitochondrial depolarisation: The loss of membrane potential across the inner mitochondrial membrane, leading to impaired ATP synthesis and cell death.

ATP (adenosine triphosphate): The principal energy carrier in cells, produced by glycolysis and mitochondrial oxidative phosphorylation.

References

1. A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1. Proceedings of the National Academy of Sciences of the United States of America (2024).
2. Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease. npj Parkinson's Disease (2023).
3. AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins. Scientific Reports (2023).
4. Association of Glycolysis-Enhancing α-1 Blockers With Risk of Developing Parkinson Disease. JAMA Neurology (2021).