Astrocytic metabolic reprogramming in Parkinson’s disease: mechanistic crosstalk and therapeutic opportunities

Parkinson's disease (PD), a neurodegenerative disorder, is predominantly characterized by the depletion of dopaminergic neurons in the substantia nigra pars compacta and the aberrant aggregation of α-synuclein (α-syn). Recent research has indicated that astrocytes not only function as indispensable supportive cells for the maintenance of central nervous system homeostasis but also act as crucial pathological regulators in the onset and progression of PD. In the context of PD pathology, astrocytes experience substantial metabolic reprogramming, primarily characterized by the dysregulation of glucose, lipid, and amino acid metabolism. These alterations may include context-dependent changes in glycolytic activity and mitochondrial respiration, disturbances in lipid transport and peroxidation defense, and impairments in the glutamate-glutamine cycle and glutathione metabolism. These alterations may compromise astrocytic metabolic support, antioxidant defense, and neurotransmitter homeostasis, thereby increasing neuronal vulnerability. This review examines changes in astrocytic glucose, lipid, and amino acid metabolism and how they intersect with α-syn proteostasis. We highlight a potential bidirectional interplay in which α-syn pathology may disrupt astrocytic metabolism, whereas astrocytic dysfunction, including impaired metabolic support and α-syn clearance, may further exacerbate neuronal pathology. Finally, we discuss therapeutic opportunities for modulating astrocytic metabolism and consider the challenges of translating preclinical findings into clinical interventions.