Study Rationale:
Astrocytes are important cells in the brain. They play a major role in brain inflammation and neurodegeneration; however, their role in Parkinson's disease (PD) is unclear. The protein alpha-synuclein, which is associated with PD pathology, can trigger the reactivity of astrocytes. The goal of the project is to understand the molecular and functional consequences of alpha-synuclein-induced astrocyte reactivity and inflammation in experimental models of PD.
Hypothesis:
We hypothesize that brain inflammation plays an important role in PD, acting either as a trigger of the disease or as a modulator of its progression, and that it is in part mediated through alpha-synuclein-astrocyte interactions.
Study Design:
We will differentiate induced pluripotent stem cells ("man-made" stem cells that can become different types of cells) generated from individuals with familial and idiopathic PD into astrocytes. We will then treat the astrocytes with chemical stressors and alpha-synuclein and examine the molecular and functional changes triggered by the treatments.
Impact on Diagnosis/Treatment of Parkinson's disease:
The project will allow us to clarify the role of astroglial reactivity and inflammation and gene-environment interaction as a potential trigger of familial and idiopathic PD.
Next Steps for Development:
Our work may lead to the identification of new disease pathways, which could be targeted for neuroprotection, and identify astrocytes as a new therapeutic target for PD.
Final Outcome
Neuroinflammation is a process that accompanies neurodegeneration and involves several types of cells, including brain cells called astrocytes and immune cells. Protein alpha-synuclein is naturally produced during brain development and is required for it to function properly. In Parkinson's disease (PD), however, alpha-synuclein clumps and spreads throughout the brain as the disease progresses. We hypothesized that alpha-synuclein may participate in neuroinflammation in PD by promoting the release of proinflammatory cytokines, molecules that support inflammation. This, in turn, could affect the survival and function of brain cells over time. We tested our hypothesis using astrocytes created from stem cells donated by healthy people and by people with Parkinson's with either genetic or unknown causes. When treated with alpha-synuclein, astrocytes could produce proinflammatory cytokines and showed changes in several genes. These data clearly indicate that astrocytes respond to alpha-synuclein, implying they may participate in Parkinson's disease.