Glial pathology and energy metabolism changes in the brain precede symptoms of Parkinson’s disease (PD) and multiple other neurodegenerative diseases. Astrocytes govern and regulate a large part of the energy metabolism in the brain. Prolonged impairment of astrocytic functions could increase the vulnerability of dopaminergic neurons in the substantia nigra (SN). In this model, 40‑50% of dopaminergic neurons were selectively killed, causing transient locomotor disability compensated with time. We also induced death of astrocytes in the SN, simultaneously activating microglia but sparing the dopaminergic neurons. The astrocytes replenished after toxin withdrawal. We studied multiple markers of energy metabolism and mitochondrial oxidative phosphorylation (OxPhos) complex and supercomplex functioning during the early stages of neurodegeneration and compensation in the SN and striatum (STR). Death of astrocytes diminished the capability of the dopaminergic system to compensate for the degeneration of neurons. It caused a local energy deprivation, a shift in the usage of energy substrates, via increased glycogenolysis and glycolysis markers, ketone bodies availability, and fatty acid transport in remaining glial cells. Increased neuronal expression of CPT1c and astrocytic expression of CPT1a suggest adaptation in fatty acid use. On the other hand, lesion of dopaminergic neurons influenced OxPhos system and enhanced its functioning. Microglia activation also plays an important role in the processes of degeneration, compensation, and energy metabolism regulation. Modulation of its activation phenotypes might be beneficial towards the indicated processes. Astrocyte and microglia energetic influence is one of the factors in the neuronal compensatory mechanisms of dopaminergic system and might have a leading role in presymptomatic PD stages.
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