Funding from The Parkinson Alliance helped to finance the following Parkinson’s research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.
Project Title: Does Air Pollution Increase the Risk of Parkinson’s Disease (PD)?
Principal Investigator(s): Jeff Bronstein MD, PhD
Objective/Rationale: The causes of PD are largely unknown. Genetic factors appear to contribute approximately 20% to risk of developing the disease leaving environmental factors likely contributing the majority of risk. A few environmental factors such as pesticides and head trauma almost certainly contribute to some individuals’ disease, these cannot explain the majority of risk that has yet been accounted for. A recent study in Denmark found those exposed to high air pollution were at increased risk of developing PD and could account for a large percentage of the PD patients. We have exciting preliminary data that support this theory. Our objective in this proposal is to determine the biological plausibility of air pollution as a risk factor for PD and how it might cause it.
Project Description/Methods/Design: Diesel exhaust particles (DEP) is the major toxic constituent in air pollution and we will use an extract of DEP in our studies. Zebrafish offer several advantages to other animal models including the fact that they are transparent and easily modified genetically. Since alpha-synuclein accumulates in neurons in PD, we will test the effect of DEP on expression of alpha- synuclein using quantitative PCR and immunoassays. We will also determine the effect of DEP on other proposed pathogenic pathways such as inhibition of protein breakdown, inflammation through microglia, and mitochondrial dysfunction.
Relevance to Treatment of Parkinson’s Disease: There are still no treatments that slow or stop the progression of PD despite several attempts. One reason for this is that we still do not know the causes of PD which is necessary to target specific pathways. Based on extrapolation from the Danish study, more than half of all PD cases in Los Angeles could be caused by air pollution. If this is found to be accurate, we will have identified new therapeutic targets.
Expected Outcome: We anticipate that air pollution increases the risk of developing PD by more than one mechanism. We have already found that DEP causes dopaminergic neuron loss in zebrafish and preliminary studies suggest that it increases alpha-synuclein expression. Inflammation via microglia also likely contributes to the development of PD. We will also determine if air pollution’s toxicity is dependent on alpha-synuclein since many disease modifying therapies are directed at lowering alpha-synuclein toxicity.
September 2017 Project Update:
Epidemiological studies have implicated air pollution (AP) as a risk factor for developing PD and we are using various models to determine mechanisms by which it acts. Extracts of diesel exhaust particles (DEPe) contain many of the suspected toxic components of AP and were used for all experiments.
In human SH-SY5Y cells, DEPe exposure led to an increase in expression (mRNA) of α-synuclein, a central protein in the pathogenesis of PD. In primary rat mesencephalic cultures, DEPe exposure led to an increase in α-synuclein protein levels in dopaminergic neurons. Since increased levels of α-synuclein expression and protein levels have been clearly demonstrated to increase the risk of developing PD in humans, these data provide one potential mechanism for DEPe neurotoxicity.
Zebrafish (ZF) offer a unique opportunity to study mechanism of toxicity given that they are transparent and can be easily manipulated genetically. We have found that DEPe exposure leads to dopamine neuron loss in ZF but unlike mammalian cells, it did not increase the expression (mRNA) of the ZF equivalent of α-synuclein, γ1-synuclein. Despite this, we did find an increased level of γ1-syn aggregates in DEPe-treated ZF. We hypothesized that these increased levels are due to decreased breakdown of the protein. The ubiquitin proteasome degradation system was 1st tested but was unaffected by DEPe. Using a newly developed transgenic ZF model (HuC-GFP-LC3) of the other degradation system (autophagy), we found marked alterations. We are confirming these alterations using a newly developed assay of autophagic flux but if confirmed, these findings could explain the accumulation of γ1-syn and DEPe neurotoxicity in ZF.
Another important pathway implicated in PD is inflammation. Using a transgenic ZF with labeled microglia (inflammatory cells in the brain), we found that DEPe markedly activates these cells. Using genetic knockdown techniques and anti-inflammatory drugs, we are currently testing if microglia activation is responsible for at least some of DEPe toxicity to dopaminergic neurons.
In summary, we have found that DEPe exposure results alterations in a number of processes implicated in the pathogenesis of PD including increased levels of synuclein protein, disruption in protein degradation and induction in brain inflammation. These studies add further support for the hypothesis that AP increases the risk of PD which could account for a large portion of PD cases. Ongoing studies will determine which of these processes are essential mechanisms of DEPe toxicity and then we will target them with potential treatments. These studies ultimately will provide important evidence that AP contributes to the development of PD so people can lower their exposure and provide legislators with additional evidence of the dangers of AP. The mechanistic studies will guide us by providing targets for the development of treatments that slow or stop PD progression.
Air Pollution and Risk of Parkinson’s Disease: Mechanistic Studies (2017). L. Barnhill, S. Khuansuwan, H. Murata, J. Araujo, JM. Bronstein. Movement Disorders (in press), Parkinson Study Group, Ft Myers Fl.
Extracts of diesel exhaust particles increase expression of α-synuclein. L. Barnhill, S. Khuansuwan, J. Araujo, JM. Bronstein (in preparation).
Diesel exhaust extracts cause dopaminergic neuron damage by impairing autophagy. L. Barnhill, S. Khuansuwan, H. Murata, J. Araujo, JM. Bronstein (in preparation).