Activation of Microglial LRRK2 by Alpha-synuclein: LRRK2 Pathogenesis in Idiopathic PD
LRRK2 Role in Idiopathic Parkinson's Disease, 2014
Alpha-synuclein is a protein that plays an important role in all forms of Parkinsonís disease (PD). Recent data demonstrate that brain cells can secrete alpha-synuclein and that this protein can then induce inflammation within the brain. This project will examine the role of LRRK2, another protein associated with PD, in this neuro-inflammatory process and how it is linked to progression of the disease.
Microglia are the resident immune cells of the brain. They express high levels of LRRK2 and can be activated by exposure to alpha-synuclein. The role of LRRK2 in brain inflammation will be examined in microglial cell culture systems and in pre-clinical models that use alpha-synuclein to induce inflammation within the brain. This work will include the use of state-of-the-art DNA sequencing technology to identify the signaling pathways that are controlled by LRRK2 and activated by alpha-synuclein. In addition, LRRK2 inhibitors, which are potential therapeutic agents, will be tested for their impact on alpha-synuclein-induced brain inflammation.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
Idiopathic Parkinsonís disease, typically defined as those cases with no family history, invariably involves dysregulation of the alpha-synuclein protein. We will examine whether alpha-synuclein influences LRRK2 function to promote PD progression and brain inflammation and test the hypothesis that LRRK2 inhibitors may have value to idiopathic PD patients.
This project will identify molecular pathways within microglia that are activated by alpha-synuclein and analyze how they are regulated by LRRK2. This work may indicate a potential use of LRRK2 inhibitors for idiopathic PD patients, as well as identify other targets for future therapeutic intervention and disease modification.
Associate Professor of Neurology at Brigham and Women's Hospital and Harvard Medical School
Location: Boston, Massachusetts, United States