$6.6 Million Grant Will Fund Research Into Environmental Cues That May Trigger Parkinson’s

grant awarded

Scientist Kim Tieu, PhD has received a $6.6 million grant to investigate the environmental factors that may trigger the death of brain cells in Parkinson’s disease, and to develop therapies that prevent their loss.

The grant from the National Institute of Environmental Health Sciences (NIEHS) is part of its Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program. It provides funding for eight years so that researchers can tackle challenging, but potentially revolutionary, lines of research.

Parkinson’s disease is characterized by the death of dopaminergic-neurons, a class of neurons that produce the neurotransmitter dopamine. Neurotransmitters are substances produced in response to nerve signals that act as chemical messengers and allow nerve cells to communicate.

While a small percentage (less than 10%) of all cases of Parkinson’s disease can be attributed to genetic mutations, in most cases, the cause of the disease is unknown. Environmental factors, which have been strongly associated with Parkinson’s disease, are the focus of Tieu’s research.

“We know that the environment plays a crucial role in overall health, including the brain, and that exposures to environmental toxicants, most likely in combination with an individual’s genetic makeup, may lead to all sorts of diseases, including Parkinson’s,” Tieu, a professor at Stempel College of Public Health and Social Work in Miami, Florida, said in a press release.

“Some of the environmental factors that we will study are manganese and pesticides to better understand how they promote the accumulation and spread of toxic proteins in the brain,” Tieu said.

Recently, Tieu’s team reported the involvement of dynamin related protein-1 (Drp1) in Parkinson’s disease. Drp1 functions to split mitochondria (cells’ powerhouses). Researchers found that inhibiting Drp1 improves dopamine’s release and reduces neurodegeneration in mouse models of Parkinson’s disease.

Now, researchers want to investigate the role of Drp1 in the accumulation of toxic proteins involved in Parkinson’s disease and how different types of brain cells (namely glial cells and neurons) and genetic variants may render neurons more susceptible environmental toxins.

Recent evidence suggests that bacteria in the gut (known as the gut microbiome) may trigger Parkinson’s disease, a relatively new area of research that also will be the focus of Tieu’s lab.

“New evidence suggests that the accumulation of toxic protein in Parkinson’s disease may not start from the brain itself, but rather may spread from the gut. This is something that we need to investigate further and try to stop it,” Tieu said.

By exploring different avenues that may underly the development of Parkinson’s disease, Tieu hopes new therapies may be developed.

The R35 RIVER grant is given to outstanding investigators in environmental health sciences, giving him (professor Tieu) and his lab the freedom to do research over several years with the support of NIEHS,” said Tomás R. Guilarte, dean of Stempel College.

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Role of Environmental Factors in Parkinson’s Development Investigated in Review Study

environmental causes

The hallmark presence of Lewy bodies in the pathway related to sense of smell and in the gut years before a Parkinson’s diagnosis, as well as the potential cumulative impact of different triggers, may help researchers understand the environmental factors that contribute to the development of the disease, according to a review study.

The study, “The Search for Environmental Causes of Parkinson’s Disease: Moving Forward,” appeared in the Journal of Parkinson’s Disease.

Environmental factors contribute at least partially to late-onset sporadic Parkinson’s disease. Because neurodegenerative changes are too advanced to be stopped or reversed by the time a diagnosis is reached, understanding modifiable risk factors that can help to identify the disease and allow for an early intervention may lead to more successful treatment of Parkinson’s, the neurological disease with the fastest-growing prevalence.

“The greatest risk factors for [Parkinson’s] are likely environmental and not genetic,” Honglei Chen, MD, PhD, from Michigan State University, and Beate Ritz, MD, PhD, from the University of California Los Angeles, said in a press release. “Yet we know relatively little about environmental causes or triggers. Identifying these and defining ways to reduce their impact will be great research challenges for the coming two decades.”

Environmental factors may trigger Parkinson’s or modify its progression during the prodromal (early) stage, in which early symptoms or signs are present, but clinical diagnosis is not yet possible. Among the reported factors, smoking, coffee, exercise, plasma urate, and use of ibuprofen have been linked to a lower risk of Parkinson’s, while pesticide exposure and traumatic brain injury have been associated with a greater risk.

Apart from two pesticides known as rotenone and paraquat, researchers have had difficulties in providing evidence that other risk factors can cause the disease. Reverse causation — meaning that Parkinson’s changes lifestyle and behavior before a clinical diagnosis rather than the other way around — has been proposed as an explanation for the link between these environmental triggers and Parkinson’s in its early stages.

“This prodromal stage is of major interest for prevention efforts,” the researchers said in the release, adding that the discovery of Lewy bodies — protein aggregates mainly composed of alpha-synuclein that are characteristic of Parkinson’s — in the olfactory pathway and the digestive tract made targeting factors that enter the body via the nose or gut “even more important.”

The Braak hypothesis presents a potential explanation for environmental contributions in Parkinson’s prodromal development. It suggests that Lewy pathology starts in the brain’s olfactory bulb — an area of the brain involved in the sense of smell — or in enteric (gut) nerves (nerve cells that control the function of the gastrointestinal tract) years, if not decades, before reaching the substantia nigra — an area of the brain key in the control of movement that shows progressive loss of dopamine-producing neurons in Parkinson’s disease.

Findings such as a reduced sense of smell and constipation years before a Parkinson’s diagnosis have supported the Braak hypothesis. Pesticides and other environmental toxins such as air pollutants, of which there is growing evidence of harmful effects on cognitive function, organic solvents, and meats cooked at high temperatures may lead to Parkinson’s through these pathways, although a proinflammatory gut microbiome — the community of bacteria, viruses and fungi that lives in the gut — has also been proposed as a potential starting point. Certain genetic factors may also interact with these environmental causes to boost the risk for the disease.

Besides the Braak hypothesis, the scientists also discussed reported epigenetic differences — alterations in gene function but not in the DNA sequence itself — in the blood and saliva of people with Parkinson’s as well as the importance of lifelong exposure to environmental triggers.

The exposome, which refers to all environmental exposures over a lifetime, suggests that multiple environmental stimuli combine to increase the risk of Parkinson’s. This has been shown with traumatic brain injury and paraquat exposure, and with smoking combined with factors such as caffeine intake and physical activity.

“We are at an exciting moment to unveil environmental contributions to [Parkinson’s] development and progression by taking a life-course approach, and utilizing novel tools to assess environmental exposures,” the researchers said.

While they caution that the long duration of the prodromal stage complicates understanding the extent to which environmental factors contribute to Parkinson’s, the investigators “nevertheless believe it will be possible to assess long-term exposures through large-scale environmental monitoring and by using novel biomarkers that reflect the exposome.”

Both the Braak hypothesis and the exposome concept provide “a theoretical framework for scientists to design future studies to decipher the environmental causes of [Parkinson’s] and develop early interventions to halt the progression to the characteristic motor dysfunction in [Parkinson’s],” they concluded.

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Low Doses of Herbicide and Lectins Led to Parkinsonism in Animals, Study Reports

pesticides and herbicides

Ingesting a once widely used herbicide called paraquat along with lectins — proteins in common foods that bind carbohydrates (e.g., sugars) — can lead to symptoms typical of Parkinson’s disease and known as parkinsonism, a study reported.

Importantly, this animal research provides a new preclinical model for testing treatments in forms of Parkinson’s disease influenced by environmental factors.

The study, “Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat,” was published in the journal Parkinson’s Disease.

Parkinson’s development in people has been linked to both genetic and environmental factors. Researchers need to model how these factors cause the disease to discover treatments for patients with different types of Parkinson’s.

Previous studies have modeled how high levels of individual neurotoxins and external factors such as diet are linked to Parkinson’s. But individuals, over the course of a lifetime, are more likely to be repeatedly exposed to low doses of toxins, or a combination of toxins, whose disease-causing capacity may be enhanced by factors that include diet.

For example, paraquat — a neurotoxin and herbicide once in wide use and still in restricted use in the U.S. though banned in Europe — has been linked to Parkinson’s disease (ways it can be ingested include drinking water). But it has only been studied in isolation and at doses far beyond those commonly encountered. Similarly, lectins — sugar-binding proteins commonly found in legumes and grains — have been linked with rare forms of parkinsonism.

For these reasons, researchers at Penn State College of Medicine sought to understand and model how repeated exposures to low doses of toxins and external factors contribute to Parkinson’s development. They sought to demonstrate how exposure to common levels of paraquat and lectin can induce disease symptoms.

The researchers applied low-level doses of paraquat and lectins to rats daily for a week, and after a couple of weeks, checked for symptoms of parkinsonism. They tested the animals for motor function and for the production of a misfolded protein called alpha-synuclein that is linked with the development of Parkinson’s disease. They detected a decrease in motor function and in the number of dopaminergic neurons (those that produce the brain signaling chemical dopamine), the generation of misfolded alpha-synuclein, and other symptoms typical of parkinsonism.

To confirm that the symptoms spotted were related to parkinsonism, the researchers performed tests to see if known Parkinson’s treatments — levodopa — could reverse the observed symptoms.

“After observing that these animals did indeed show symptoms of Parkinsonism, we wanted to double check and make sure we weren’t looking at animals that had these symptoms for another reason,” Thyagarajan Subramanian, a study co-author and professor of neurology at Penn State College of Medicine, said in a press release. “We administered levodopa … [and] saw a return to almost normal types of motor responses, which was a clear indication that we were looking at some sort of Parkinsonism.”

Increasing evidence suggests that environmental neurotoxins or misfolded alpha-synuclein proteins are transported from the gut to the brain through the vagus nerve — the nerve that enables communication between the gut and the brain— this way damaging dopaminergic neurons in the substantia nigra, a major brain region affected in Parkinson’s disease.

“We were able to demonstrate that if you have oral paraquat exposure, even at very low levels, and you also consume lectins — perhaps in the form of uncooked vegetables, dairy or eggs — then it could potentially trigger the formation of this protein alpha-synuclein in the gut,” Subramanian said. “Once it’s formed, it can travel up the vagus nerve and to the part of the brain that triggers the onset of Parkinson’s disease.”

Interestingly, removing the vagus nerve before exposing the animals to paraquat and lectins protected them from parkinsonism.

The researchers plan to test whether medical treatments or dietary modifications can interfere with the transport of alpha-synuclein from the gut to the brain via the vagus nerve in this new model of Parkinson’s incorporating environmental factors.

They intend to test a substance called squalamine, which has been shown to remove alpha-synuclein from the gut and is now in clinical trials for treating Parkinson’s symptoms. 

“This study gives solid evidence that lectins, while in the presence of certain toxins, may be one potential culprit for the cause of Parkinsonism,” Subramanian said. “Additionally, this animal model can be a tool in the future to continue developing new medications and treatments for Parkinson’s disease.”

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Appendix Removal Early in Life Reduces Risk of Developing Parkinson’s, Study Shows

appendix, Parkinson's risk

The healthy human appendix contains Parkinson’s disease-related alpha-synuclein aggregates, and removing the organ early in a person’s life reduces the risk of developing the disease, a study has found.

The study, “The vermiform appendix impacts the risk of developing Parkinson’s disease,” was published in Science Translational Medicine. The work was led by researchers at the Center for Neurodegenerative Science at the Van Andel Research Institute in Michigan.

“Our results point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies that leverage the gastrointestinal tract’s role in the development of the disease,” Viviane Labrie, PhD, an assistant professor at Van Andel and senior author of the study, said in a press release.

In the brains of Parkinson’s patients, there is a buildup of a protein called alpha-synuclein that forms clumps known as Lewy bodies. These clumps are toxic and lead to neuronal death.

“Gastrointestinal (GI) dysfunction is a common nonmotor symptom of PD [Parkinson’s disease], often preceding the onset of motor symptoms by as many as 20 years,” the researchers wrote.

In addition, it has been shown that neurons innervating the intestines of Parkinson’s patients contain aggregated alpha-synuclein.

“Accumulation of alpha-synuclein in the GI tract not only may contribute to the nonmotor symptoms of PD but also has been hypothesized to contribute to PD pathology in the brain,” the researchers said.

Studies have revealed the existence of many alpha-synuclein aggregates in the appendixes of early-stage and established Parkinson’s patients, as well as in neurologically intact subjects.

The appendix — a worm-like organ that sticks out of the large bowel in the lower right side of the abdomen — helps the immune system detect and eliminate harmful microorganisms, while regulating the gut’s bacterial composition.

In this study, researchers investigated whether this tiny organ contributes to Parkinson’s disease risk.

They analyzed two separate, yet complementary, epidemiological data sets: the nationwide Swedish National Patient Registry (SNPR) and the Parkinson’s Progression Markers Initiative (PPMI).

The SNPR contains information on 1.6 million individuals with a follow-up period of up to 52 years. Investigators identified all individuals who had had an appendectomy (surgical removal of the appendix) from 1964 to 2015 and obtained data on their surgical procedure, year of birth, year of surgical procedure, sex, geographic location (municipality), and, when applicable, date and cause of death. For each patient who underwent an appendectomy, there were two control participants who had not had their appendix removed matched in year of birth, sex, and geographic area.

This data-set analysis revealed that appendix removal was associated with a 19.3% lower risk of developing Parkinson’s than controls. Parkinson’s was diagnosed in 1.17 out of every 1,000 patients who had an appendectomy compared with 1.4 per 1,000 in the general population.

The surgery had the greatest impact on those living in rural areas, with a significant 25.4% reduction in Parkinson’s risk, indicating that removal of the appendix might influence environmental risk factors for the disease. Interestingly, no appendectomy-related benefit was observed in the urban area sample.

“The age of PD diagnosis was, on average, 1.6 years later in individuals who had an appendectomy occurring 20 or more years prior than in cases without an appendectomy. We also observed a significant delay in age of PD onset in individuals with an appendectomy 30 or more years prior, but a limited size in this longer latency group precluded further analysis,” the scientists said.

Researchers then looked at the PPMI data set, which contained detailed information about Parkinson’s diagnosis, age of onset, and other demographic factors, as well as the genetic information of 849 patients.

The team chose to focus on individuals who had their appendix removed at least 30 years before being diagnosed with Parkinson’s, because the early-stage phase of Parkinson’s can last for decades before an accurate diagnosis.

Results showed that age at disease onset was significantly delayed by 3.6 years in those who had undergone an appendectomy (54 individuals, representing 6.4% of the Parkinson’s sample), compared with those who had not.

Disease occurrence was not linked to immune disorders not affecting the gastrointestinal tract, nor was it related to the surgical event itself.

Once a Parkinson’s diagnosis had been established, there were no differences in symptom severity between people with and without a history of appendectomy, suggesting the appendix can potentially impact disease mechanism before the clinical onset of symptoms.

The team then explored the interaction between the appendix and environmental/genetic Parkinson’s risk factors. They reported that the surgical procedure delayed the age of onset in subjects with a family history — meaning those with one or two family members with Parkinson’s — but had no effect in individuals without a family history of the disease.

Importantly, those with a mutation in the LRRK2GBA, or SNCA gene — which are common in hereditary Parkinson’s cases — did not benefit from the appendectomy, indicating that removal of the appendix may be more protective against environmental causes of Parkinson’s rather than genetic ones.

Tissue analysis showed that the mucosa and neurons within the healthy human appendix were filled with aggregated alpha-synuclein. Such accumulation was evident in all age groups, including subjects younger than 20.

Although appendixes of both people with and without Parkinson’s contained disease-prone forms of alpha-synuclein that tend to aggregate rapidly, the Parkinson’s group’s “diseased” protein content was higher than that of the control group.

“We were surprised that pathogenic forms of alpha-synuclein were so pervasive in the appendixes of people both with and without Parkinson’s. It appears that these aggregates — although toxic when in the brain — are quite normal when in the appendix. This clearly suggests their presence alone cannot be the cause of the disease,” Labrie said.

Next, the scientists will search for which appendix-related factor(s) may contribute to Parkinson’s disease.

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First-degree Relatives at Higher Risk of Parkinson’s, Other Neuropsychiatric Disorders, Study Finds

first-degree relatives risk

First-degree relatives of Parkinson’s patients are more likely to develop the disease and are at a higher risk for other neuropsychiatric disorders, a study shows.

The study, “Familial aggregation of Parkinson’s disease and coaggregation with neuropsychiatric diseases: a population-based cohort study,” was published in Clinical Epidemiology.

Most Parkinson’s cases are considered to be sporadic, but several studies have suggested that the disease results from a combination of genetic and environmental factors.

Several genes have been pinpointed as the cause of 6 to 7 percent of the clinical variability observed in Parkinson’s disease.

To better understand the impact of genetic and environmental factors on the development of Parkinson’s, researchers reviewed potential risk factors that could be linked to familial aggregation of the disease.

Clinical records of all individuals registered in the Taiwan National Health Insurance Research Database in 2015 were analyzed. Of the total registered population of 24,349,599 individuals, 112,037 were diagnosed with Parkinson’s disease.

This included 149,187 individuals who had a parent affected by Parkinson’s, 3,698 with an affected offspring, 3,495 with an affected sibling, and 15 individuals with an affected twin.

Researchers found that individuals who had a first-degree relative with Parkinson’s disease had a 1.69 times increased chance of also developing the disease. This risk was similar for both male and female relatives and was greater for twins, who were 63.12 times more likely to develop Parkinson’s.

The risk of developing Parkinson’s was 2.2 times higher for siblings, 1.86 times higher for offspring, 1.59 times higher for parents, and 1.46 times higher for spouses.

These results suggest that the clinical variability of Parkinson’s prevalence observed in the Taiwanese population is accounted for by genetic factors (heritability) at 11%, shared environmental factors at 9.1%, and non-shared environmental factors at 79.9%.

Additional analysis further showed that first-degree relatives of Parkinson’s patients are also at an increased risk for some other neuropsychiatric disorders than the general population. These include major depression, anxiety, multiple sclerosisAlzheimer’s disease, and amyotrophic lateral sclerosis, among others.

Researchers believe that Parkinson’s disease “should be considered an age-related multifactorial syndrome with mainly genetic and environmental components.”

“First-degree relatives of PD patients are more likely to develop PD and other neuropsychiatric diseases. Environmental factors account for a high proportion of the pheno- typic variance of PD,” they wrote.

“Our findings provide information useful for counseling families of Parkinson’s patients,” they also said.

Additional studies are still needed to identify the environmental causes responsible for Parkinson’s susceptibility, and the genetic contribution for disease variability remains to be determined in other populations.

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