Glycolytic Reprogramming in Parkinson's Disease: From Bioenergetic Crosstalk to Therapeutic Modulation

Parkinson's disease (PD) is increasingly recognized not merely as a localized proteinopathy, but as a systemic metabolic disorder driven by bioenergetic failure. While mitochondrial dysfunction is a well-established pathological hallmark, the compensatory reprogramming of glycolysis has emerged as a critical, yet double-edged, determinant of neuronal survival. This review critically examines the molecular and spatial architecture of glucose metabolism in the parkinsonian brain. We systematically dissect how upstream genetic regulators, including PTEN and PARK7/DJ-1, alongside downstream rate-limiting enzymes orchestrate the glycolytic shift in response to mitochondrial collapse and α-synuclein proteotoxicity. Moving beyond a neuron-centric view, we highlight cell-specific metabolic compartmentalization, emphasizing the disruption of the astrocyte-neuron lactate shuttle and the divergent glycolytic phenotypes of reactive microglia. Crucially, we evaluate the dual nature of glycolytic metabolites by demonstrating that a moderate flux sustains basal energy requirements and prevents apoptosis, whereas unchecked hyperglycolysis drives secondary pathological cascades through methylglyoxal-induced protein crosslinking and lactate-mediated neuroinflammation. By bridging these mechanistic insights with cross-disease metabolic links to type 2 diabetes and oncology, we evaluate the therapeutic potential of emerging metabolic modulators, including terazosin, cordycepin, and GLP-1 receptor agonists. Finally, we outline the pressing translational bottlenecks, particularly blood-brain barrier penetrance and cell-specific targeting, which must be overcome to successfully harness glycolytic modulation as a disease-modifying strategy for neurodegenerative disorders.