Fig. 2

The brain RAS plays a role in the progression of dopaminergic neuron degeneration. Different pathogenic factors may trigger molecular and cellular changes that lead to an initial dysregulation of the brain RAS, or dysregulation of the dopaminergic neuron function leading to decreased dopamine production, which affects the dopamine/RAS interaction in neurons and glial cells. In neurons, a decrease in dopamine level upregulates the angiotensin type-1 (AT1) receptor activity, leading to the recovery of dopamine levels together with overactivation of the NADPH-oxidase-superoxide-mitochondria axis and Ca²⁺ release, which mediate several key events such as oxidative stress, α-synuclein aggregation, and neuroinflammation involved in the progression of Parkinson's disease (PD). An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivation (detailed in Fig. 3). In microglial cells, AT1 receptor upregulation activates the NADPH-oxidase complex, increasing the release of ROS to the extracellular space and the inflammatory response. In astrocytes, a decrease in dopamine level induces an increase in paracrine angiotensinogen/AngII production that can act on neurons and microglial cells. AngII, angiotensin II; AT1, angiotensin type I; ROS, reactive oxygen species