Study Rationale:
The hallmark motor impairments in Parkinson’s disease patients are due to the progressive loss of a special type of neuron in the brain using the chemical messenger dopamine. The mechanisms leading to their destruction during disease progression are not well known. An emerging concept in the field of Parkinson’s disease is that the immune system plays a role in the progressive death of these neurons.
Hypothesis:
We hypothesize that Parkinson’s disease is initiated years before the emergence of motor dysfunction in response to mechanisms triggered following gut infection with Gram-negative bacteria. This leads to an autoimmune reaction producing specialized immune cells that can reach the brain and attack dopamine-producing neurons.
Study Design:
We will study how mutations in proteins associated with Parkinson’s disease (PINK1, Parkin, LRRK2, VPS35 and GBA) affect the function of immune cells in isolated cell culture (in vitro), as well as in mouse models of Parkinson’s disease. In the model, we will characterize how the immune system is stimulated during gut infection to produce cytotoxic T lymphocytes, and how these cells reach the brain and attack dopamine-producing neurons. Similar studies will also be done with immune cells from the blood of Parkinson’s disease patients and neurons derived from stem cells.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The involvement of the immune system in Parkinson’s disease suggests that novel types of therapeutic approaches targeting immune cells could be developed to slow the progression of the disease or even prevent it early on before the emergence of motor impairments.
Next Steps for Development:
Findings from this study will be further interrogated to nominate therapeutic targets and propose drug candidates. Interestingly, drugs already approved for use in other diseases might turn out to have the capacity to inhibit the autoimmune processes presumably leading to Parkinson’s disease pathology.