Airborne Pollutants as Triggers of Parkinson s Disease via the Olfactory System
Abstract
Due to the nature of its function, the olfactory system (which controls our sense of smell) is naturally exposed to external environmental factors. The air we breathe contains extremely small and harmful particles (so-called pollutants) that can, through the nose, reach the brain. Studies have shown that the brains of people that are constantly breathing pollutants resemble the brains of people with Parkinson’s disease (PD). It is believed that pollutants trigger a reaction in the brain called inflammation and that this inflammation, in turn, promotes changes in the brain (see below) that lead to PD. In line with this idea, Dr. Chen showed that people that used anti-inflammatory drugs, like ibuprofen, had a lower risk of developing PD later in life than other people. PD is characterized by the accumulation of abnormal alpha-synuclein (a-syn) that forms aggregates (clumps) in the brain. It is unclear why a-syn, which is a protein of unknown normal function, changes, adapting an abnormal shape and starts to aggregate. The olfactory system is one of the first regions in the brain in which a-syn aggregates develop. Interestingly, a reduction in the ability to smell often precedes the most typical symptoms of PD. It is, therefore, believed that changes in the ability to smell are caused by the presence of a-syn aggregates in the olfactory system. Taken together, we propose that inflammation caused by airborne pollution leads to the formation of a-syn aggregates in the olfactory system, which eventually leads to PD. To test the idea that a-syn aggregates are the cause of the loss of smell in PD, Dr. Brundin’s lab members developed a system using mice that “artificially” recreated the process. They injected small fragments of a-syn protein aggregates into the olfactory bulb, which is a brain structure that exhibits some of the first changes in PD. These fragments worked as “seeds,” causing the accumulation of the a-syn that is naturally found in the olfactory bulb. We believe that these “seeds” are able to transform the normal a-syn into abnormal a-syn. Once the transformation occurs, a-syn starts to accumulate. Importantly, over time the aggregates begin to appear in other brain structures connected to the olfactory bulb, as it is believed to occur in PD. Notably, as the number of aggregates throughout the olfactory system and other brain regions increased, the sense of smell of the mice deteriorated. In parallel, Dr. Finch’s lab developed a model in which the type of inflammation caused by exposure to pollutants was recreated in mice. Thus, we will now combine our two models to study how exposure to pollutants affects the “artificial seeding” of a-syn and to investigate how the “artificial seeding” affects inflammation. We will also determine if ibuprofen and a novel drug (that reverses PD-like signs in mice and is called MSDC-0160) can reverse the brain damage seen in our models. We will also test our hypothesis in humans using clinical methods. By studying human populations that have been exposed to pollutants over years, Dr. Chen and collaborators will determine if there are differences between people who developed decreased sense of smell in late adulthood and people who have not. We will focus on genetic differences that are known to be related to the risk of developing PD and in the use of anti-inflammatories throughout adult life. Our proposal relates to the focus area named “Identification and evaluation of mechanisms in early Parkinson’s disease involving olfactory, microbiome, gastrointestinal, and/or autonomic nervous systems,” as we want to demonstrate that inflammation cause by pollutants and affects the olfactory system can trigger the development of PD. Our work would be relevant for the vast majority of PD patients, as exposure to pollutants affects the majority of the human population. We believe that studying these processes can identify novel ways to try to prevent the progressio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710535
Entities
People
- Caleb Finch
Organizations
- United States Army
- University of Southern California