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Funded Studies

Activation of Microglial LRRK2 by Alpha-synuclein: LRRK2 Pathogenesis in Idiopathic PD

Alpha-synuclein is a protein that plays an important role in all forms of Parkinson’s 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.

Project Description:
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 Parkinson’s Disease:
Idiopathic Parkinson’s 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.

Anticipated Outcome:
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.


  • Matthew J. LaVoie, PhD

    Boston, MA United States

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