This review synthesizes evidence that impaired brain glucose metabolism — including altered glycolysis and disrupted neuron–astrocyte metabolic coupling driven by dopamine, alpha-synuclein, and DJ-1 dysfunction — contributes to PD and evaluates strategies to restore glycolytic/energetic homeostasis.

By linking specific molecular drivers to metabolic deficits and assessing glycolysis-targeted and repurposing strategies, the paper highlights actionable therapeutic avenues with translational potential to slow Parkinson's disease progression.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and alpha-synuclein (α-syn) aggregation. Although current therapies alleviate symptoms, they fail to halt disease progression, and the underlying drivers remain elusive. Cellular metabolic dysfunction, particularly impaired glucose metabolism and reduced adenosine triphosphate production, considerably contributes to PD pathogenesis. This review systematically describes the core features of brain glucose metabolism and the cooperative metabolic network between neurons and astrocytes. Furthermore, it details specific alterations in glycolytic pathways observed in PD, elucidating the mechanisms by which key factors such as dopamine, α-syn, and DJ-1 contribute to this metabolic impairment. Finally, the review critically evaluates emerging therapeutic strategies targeting glycolysis to restore energy homeostasis, underscoring their potential as novel interventions to suppress disease progression. A deeper understanding of these metabolic mechanisms promises new avenues for developing effective PD treatments.