Diesel Exhaust Tied to Risk of Parkinson’s Disease, Fish Study Shows

diesel exhaust

Chemicals in diesel exhaust can trigger the formation of toxic protein clumps and the death of nerve cells — hallmarks of Parkinson’s disease — by preventing the cell’s natural disposal mechanisms from working properly, a study in fish and human cells shows.

The findings also demonstrated that boosting these cellular recycling mechanisms with an approved leukemia medication, Tasigna (nilotinib), reduced the neuronal toxicity caused by diesel exhaust.

The study, “Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy,” was published in the journal Toxicological Sciences.

In addition to causing respiratory and heart diseases, long-term exposure to air pollution is increasingly implicated in the development of neurodegenerative diseases, potentially accounting for environmental factors that cause disease.

The main components of air pollution in urban environments come from diesel exhaust, and research in humans and animal models has suggested that diesel exhaust contributes to neurodegeneration and protein aggregation. But the mechanisms through which diesel exhaust chemicals cause these disease features remain unknown.

To address this further, researchers at the University of California, Los Angeles (UCLA) tested the chemicals from diesel exhaust on zebrafish, a fish species that have similar neuronal networks as humans. Zebrafish are well-suited to study environmental toxins, and their transparent larvae enable researchers to easily examine brain cells in living animals.

“Using zebrafish allowed us to see what was going on inside their brains at various time-points during the study,” Lisa Barnhill, a UCLA postdoctoral fellow and the study’s first author, said in a press release.

The team added chemicals from diesel exhaust to the water in which the zebrafish were grown. Exposure to these chemicals changed how animals were moving throughout the day and caused the death of nerve cells. Parkinson’s patients experience a loss in dopamine-producing neurons, but all neurons were being affected in the zebrafish.

After excluding problems in the proteasome — a machinery in cells that degrades proteins — as the cause of neuronal death, the researchers turned their attention to another process used by cells to clear out toxic accumulations of unwanted components: autophagy. This mechanism is used to recycle cellular components, including the toxic protein aggregates seen in neurodegenerative conditions, and its function is known to be altered in Parkinson’s.

Before being exposed to the chemicals, the fishes’ neurons had tiny sacs moving around that were carrying the damaged or old components to be destroyed. During the autophagy process, these sacs merge with another component in cells, called the lysosome, that is full of powerful degrading enzymes.

“We can actually watch them move along, and appear and disappear,” said Jeff Bronstein, MD, PhD, professor of neurology and director of the UCLA Movement Disorders Program.

But after the chemical treatment, these sacs rose in numbers because they were no longer able to fuse with lysosomes. This meant that proteins and other toxic molecules were not being cleared out of cells properly, leading to nerve cell death.

The team then examined what this impairment in autophagy did to protein aggregation in nerve cells. Zebrafish do not have the alpha synuclein protein — whose aggregation into toxic clumps is a hallmark of Parkinson’s — but researchers found that exposure to the chemicals from diesel exhaust significantly increased the aggregation of another protein of the same family, synuclein gamma 1.

Finally, treatment with Tasigna, an approved leukemia therapy shown to increase autophagy in zebrafish models, was able to rescue nerve cell death in these animals, the team found.

“Although still in preliminary stages of investigation, this class of drugs has shown promise in several model systems and lends credence to the idea that impaired autophagy is a primary molecular mechanism of neurotoxicity in neurodegenerative disease,” the researchers wrote.

Overall, the findings suggest that exposure to air pollution, and particularly diesel exhaust, is able to induce features of Parkinson’s disease by impairing the normal functioning of the cells’ waste disposal. Yet, researchers believe this is not the only mechanism affected by diesel exhaust, as other studies also have reported increases in neuronal inflammation.

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Reduced Levels of Chaperone Protein May Advance Parkinson’s, Other Dementias, Study Finds

chaperone rotein levels

Low levels of a specific chaperone  protein might be implicated in the development of Parkinson’s disease and Lewy body dementia, according to new research.

The protein may be a promising therapeutic target to treat Parkinson’s, with researchers pursuing this possibility in preclinical studies.

The study, “14-3-3 proteins reduce cell-to-cell transfer and propagation of pathogenic alpha-synuclein,” was published in The Journal of Neuroscience.  

Development of Parkinson’s disease and Lewy body dementia has been tightly linked with the formation of misfolded clumps of the alpha-synuclein protein inside nerve cells. These aggregates contribute to the nerve cell death and neurodegeneration that characterize these diseases.

Once formed, misfolded alpha-synuclein clumps can be spread from one brain region to another, thereby advancing the disease. But not much has been known about the mechanisms underlying the transmission between affected and healthy nerve cells.

University of Alabama at Birmingham researchers investigated the role of a protein they thought could potentially play a part in this process. The protein, called 14-3-3θ, is a chaperone — a type of protein that can assist other proteins to assume a proper shape — highly expressed in the brain, essential for nerve cell functioning, and known to interact with alpha-synuclein. 

Proteins need to have their proper shape to interact with other structures. Failure to do so, called misfolding, can result in a number of diseases.

Researchers used both human and mouse nerve cells grown in the laboratory to investigate the role of 14-3-3θ in the formation and spread of alpha-synuclein aggregates.

Inhibiting 14-3-3θ promoted the aggregation and spread of alpha-synuclein from neuron to neuron, resulting in increased nerve cell death. Conversely, higher levels of 14-3-3θ protein blocked alpha-synuclein clump formation and limited its transfer to other nerve cells, preventing cell death.

“Our findings indicate that 14-3-3θ plays an important role in the management of alpha-synuclein, keeping it in a more normal folded state and preventing the spread of aggregates across the brain,” Talene Yacoubian, an MD and PhD, associate professor in the Department of Neurology at UAB and senior author of the study, said in a news release.

“The study suggests that 14-3-3θ may be a suitable target for efforts to slow the progression of neurodegenerative diseases, although more work is needed,” she said.

There is evidence that 14-3-3θ levels in the brain decrease as people age. Because Parkinson’s and Lewy body dementia are mostly diseases of aging, it further suggests that 14-3-3θ as a chaperone could become a potential therapeutic target.

“If subsequent research confirms our findings of its [14-3-3θ] role on preventing misfolding of alpha-synuclein, we may have a viable target for intervention in neurodegenerative diseases that are also age-related,” Yacoubian added.

The team has already began to conduct studies in animal models and is collaborating with the Southern Research Institute to find a compound suitable for human use that boosts the production of 14-3-3θ.

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Source: Parkinson's News Today

Changes in Specific Brainstem Nerve Cells Linked to Parkinson’s for First Time

brainstem cells

It’s widely accepted that Parkinson’s disease (PD) patients experience neuronal death in the brainstem. Now, for the first time, researchers report that the number of copies of mitochondrial DNA is increased in the surviving nerve cells within this area of the brain.

Interestingly, specific brainstem neurons had more alterations in their mitochondrial DNA.

“This is the only study to date to characterise mitochondrial DNA errors in cholinergic neurons, a neuronal population that is highly vulnerable to cell death in Parkinson’s disease patients,” Joanna Elson, PhD, a mitochondrial geneticist at Newcastle University, said in a press release.

The study resulted from a collaboration between Newcastle University and University of Sussex, both in the United Kingdom.

The team’s work, “Mitochondrial DNA xchanges in pedunculopontine cholinergic neurons in Parkinson disease,” was published in Annals of Neurology.

Mitochondria are our cells’ powerhouses, responsible for maintaining their health. Changes to the genetic composition of the mitochondria compromise its function and can lead to nerve cell death.

Mitochondrial DNA damage has been associated with both normal aging and neurodegeneration.

In a Parkinson’s scenario, studies have demonstrated that a specific brainstem region, known as the pedunculopontine nucleus (PPN), presents altered mitochondrial DNA.

PPN is thought to be involved in the initiation and modulation of gait and other stereotyped movements. As a result of Parkinson’s progression, these “behavioral functions” are affected.

Part of the PPN is made up of cholinergic neurons, meaning these cells produce the brain chemical acetylcholine and use it to communicate with other nerve cells. Cholinergic neuronal loss has been observed in Parkinson’s patients.

In this study, researchers isolated single cholinergic neurons from postmortem PPNs of Parkinson’s patients and aged controls. They then analyzed its mitochondrial DNA content.

Results showed that the number of copies and changes in mitochondrial DNA were significantly higher in the Parkinson’s group, compared to the control samples.

Moreover, the mitochondrial DNA of Parkinson’s patients changed by more than 60 percent, which has been associated with deleterious effects on mitochondria function.

The current results differ from other studies that have focused on other brain regions and cell types.

“Our study is a major step forwards in gaining an enhanced insight into the serious condition. Only by understanding the complexities of what happens in specific cell-types found in specific areas of the brain during this disease can targeted treatments for Parkinson’s disease be produced,” Elson explained.

“At present, treatments are aimed at the whole brain of patients with Parkinson’s disease. We believe that not only would cell-specific targeted treatments be more effective, but they would also be associated with fewer side-effects,” said Ilse Pienaar, PhD, a neuroscientist at Sussex University.

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Source: Parkinson's News Today