Astrocytes are essential for brain health. Indeed, they provide structural and metabolic support; regulate synaptic transmission; maintain glutamate homeostasis as well as produce neurotrophic molecules. In Parkinson’s disease (PD) these pathways became progressively dysfunctional thus switching to a neurotoxic phenotype. Scientific evidence suggests that neurotoxic glial cells might be responsible for neuroinflammation that plays a key role in the symptoms and development of PD. However, the mechanistic correlation among glial activation, neuroinflammatory response, dopaminergic neuronal loss and progression of PD needs to be clarified. Therefore, the main goals of this project are:To study the temporal evolution of glial cells phenotype in midbrain and striatum during the progression of the disease.To identify the genes involved in the transition from a neuroprotective to a neurotoxic glial phenotype.To address these issues Western blot analysis was performed in midbrain and striatum of 4-6-12-16-old months mice expressing the human A53T-α-synuclein, to determine pro/anti-inflammatory protein expression changes. We demonstrated that 12-months represent the time point in which the glial cells shift from neurotrophic to detrimental phenotype both in midbrain and in striatum. To further understand the molecular mechanism behind this effect, we adopted an unbiased technique guided by pre-existing single nucleus RNA-Seq database on the same animal model at an early stage. Using this method, we found two genes that are differentially expressed in the midbrain and striatum, respectively. We are currently investigating the potential role of these genes in the in astrocyte phenotypic transitions throughout the progression of PD.