Pharmacological Targeting of Proinflammatory Kinase Signaling in Parkinson's Disease

Study Rationale:
In Parkinson's disease, the brain's resident immune cells, called microglia, can become persistently activated due to the accumulation of alpha-synuclein-containing protein clumps called Lewy bodies. This constant immune activation can lead to a cycle of ongoing inflammation in the brain, which can contribute to the gradual death of brain cells and disease progression. Emerging evidence also suggests that ongoing inflammation can contribute to the accumulation and spread of the protein clumps in the brain. Therefore, halting this cycle of inflammation and cell death could prevent the worsening of the disease and potentially improve disease symptoms.

Hypothesis:
Our study attempts to interrupt the chronic inflammation cycle that drives disease progression by blocking a key kinase signaling pathway that drives inflammation in the brain. Crucially, we will utilize a clinically approved drug that has been tested in human patients and has a good safety record with long-term use.

Study Design:
We will test the efficacy of using different chemical versions of the drug to block immune activation and brain inflammation in two models of Parkinson's disease. If our studies are successful and our small molecule drug is effective, we expect to see improvements in Parkinson's-like symptoms in our disease models along with reduced dopaminergic neuron death and inflammation in the drug-treated groups.

Impact on Diagnosis/Treatment of Parkinson's Disease:
Since the drug we are testing in our Parkinson's models is already clinically approved and has been shown to be safe in humans, our studies will confirm if this drug has potential to be used in the treatment of Parkinson's disease to improve patient outcomes and slow disease progression.

Next Steps for Development:
If our studies our successful, the next steps will potentially include clinical evaluation of the efficacy of this compound in patients, to determine if this approach is effective in Parkinson's disease. Additionally, improved versions of the drugs can also be generated, which could be more effective at blocking inflammation and the loss of brain cells in Parkinson's disease.