Study Rationale:
To slow the progression of Parkinson's disease (PD), we need to know more about how it starts. It is well known now that many individuals with PD have had a significant reduction in their ability to smell years before their movement disorder starts. Here, our team will study the role of a PD-linked gene, alpha-synuclein, in odor processing, and how viruses in the nose may change how alpha-synuclein is handled within the odor-signaling cells of the brain in people with PD.
Hypothesis:
We hypothesize that certain environmental triggers, including viruses, can start a chain reaction inside the nasal cavity by which a protein called alpha-synuclein begins to form insoluble clumps. This happens inside the nerve circuits that specifically process scent and then gradually spreads further inside the brain, thereby promoting Parkinson’s disease.
Study Design:
We will first define the normal role of the alpha-synuclein protein in the scent-processing circuits of mice and humans. We will then answer whether so-called Lewy bodies (i.e., alpha-synuclein clumps in nerve cells) contribute to the inability to smell. Third, we will study the areas of the human brain that are responsible for smell, including using MRI imaging. Lastly, we will perform studies with nasal fluids from people with PD and introduce these (and viruses) into mice, to see if these start a reaction that cause changes in the mouse olfactory system like what is seen in humans with PD, including loss of smell and changes in the alpha-synuclein protein. We will see if the inability to smell can progress to motor deficits.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This study will delineate what causes the loss of sense of smell in PD. That will help us to develop new drugs to treat it and explore new ways to diagnose the disease, hopefully at a stage before the movement symptoms appear. We may also gain insights into risk factors for PD, which could lead to strategies to help people reduce their risk. We will also create new animal models that can be used by others.
Next Steps for Development:
If we are correct with our concept that the environment contributes to PD through inflammatory responses that begin with a reduced sense of smell, and are successful in proving it, we may have created a better basis to assess PD risk, establish its diagnosis, and assess its rate of progression.