The Role of FcgRIIb in Alpha-synuclein Toxicity and Spread

Study Rationale:
People with Parkinson's disease (PD) have clumps of protein alpha-synuclein in the brain. As PD progresses, these clumps spread through the brain, damaging nerve cells (neurons) that control movement, balance and speech. Neurons have on their surface protein sensors called FcγRIIB receptors, which can detect and bind to alpha-synuclein clumps, spreading the disease. If these receptors are disabled, alpha-synuclein cannot bind to the neurons. In this study, we will test whether we can block the spread of the toxic clumps in pre-clinical models. We will also test whether we can develop an antibody therapy that can prevent, or even halt, Parkinson's disease.

Hypothesis:
In this study, we aim to determine whether the toxic effect of alpha-synuclein clumps and their spread through the brain depend on FcγRIIB.

Study Design:
First, we will confirm the role of the FcγRIIB receptor in spreading the disease in neurons grown in vitro as a mini-network, similarly to neurons in the brain. The next step will be to study the role of FcγRIIB in a pre-clinical model with Parkinson's features. We will expose the brain to clumps of alpha-synuclein in normal models and in those lacking FcγRIIB and look for changes in behavior and evidence of neuronal damage. We have created an antibody, a protein that blocks the function of the FcγRIIB receptor. This antibody will be used in our models to prevent spreading of alpha-synuclein through the brain to test if this protects the brain from damage.

Impact on Diagnosis/Treatment of Parkinson's Disease:
If FcγRIIB plays a key role in spreading toxic clumps though the brain, and if blocking this process with an antibody prevents disease progression, then clinical testing of this treatment approach in people with Parkinson's could be rapidly implemented.

Next Steps for Development:
Our industry partner is already producing therapeutic antibodies targeting FcγRIIB for the treatment of cancer. These antibodies would need to be optimized for the treatment of Parkinson's disease.