Enzyme May Be Early Biomarker of Parkinson’s and Treatment Target for Patients, Scientist Suggests

sEH enzyme and Parkinson's

Ways of better diagnosing and treating Parkinson’s patients may lie in developing biomarkers, inhibitors, and stem cells therapies that are based on an enzyme newly identified in research into this disease, called soluble epoxide hydrolase (sEH), a commentary article suggests.

The opinion piece, “Fatty acid chemical mediator provides insights into the pathology and treatment of Parkinson’s disease,” was written by Cesar V. Borlongan, director of the Center of Excellence for Aging & Brain Repair at the University of South Florida, and published in Proceedings of the National Academy of Sciences (PNAS) of the United Stated of America.

Parkinson’s disease is characterized by progressive loss of brain cells — in particular, those that produce dopamine — as well as by the accumulation of abnormal protein aggregates, including alpha-synuclein and Lewy bodies.

Brain cells most affected by the disease are located in the substantia nigra, a basal ganglia structure in the midbrain that is rich in dopamine neurons, but other brain areas are also impacted both at Parkinson’s onset and throughout disease progression.

The accumulation of toxic alpha-synuclein aggregates has been pinpointed as the major player in nerve cell degeneration.

But several studies report that other mechanisms, including calcium imbalance, neuroinflammation, and increased oxygen-mediated stress, are also directly linked to Parkinson’s.

“Unfortunately, despite these scientific advances in our knowledge of the disease pathology [mechanisms], there is no cure for Parkinson’s disease, only relief from its symptoms,” Borlongan wrote.

Hs commentary focused on a recent study published in PNAS that highlighted the important role of the soluble epoxide hydrolase (sEH) enzyme plays in neuroinflammation and the death of dopaminergic nerve cells in the brain, seen by its researchers working in multiple animal models of Parkinson’s and in patients’ cells.

They demonstrated that sEH contributes to the transformation of alpha-synuclein to a toxic element in brain cells. Additional studies also show that alpha-synuclein mediates the loss of nerve cells in the periphery, suggesting that sEH — similar to what happens in the brain — may also modify alpha-synuclein in peripheral nerve cells (peripheral being the gastrointestinal track and enteric, or intrinsic, nervous system that governs that track).

Importantly, this phenomenon could occur at very early disease stages, before nerve cell damage is established.

While this discovery is important for the mechanistic and other insights it provides, it may also point to new ways of diagnosing and treating patients, Borlongan suggests.

“Whether sEH similarly initiates from the periphery and propagates to the brain in transporting α-synuclein will be of high clinical relevance, as it will allow early peripheral diagnosis of PD, which does not manifest its first motor symptoms until 80% of striatal dopamine is lost,” he wrote. “It may be possible to detect elevated sEH levels peripherally as a prelude to brain dopamine degeneration, thereby aiding in early intervention of the disease.”

For diagnosis, the research raises the possibility that increased levels of sEH in the periphery could be an early biomarker of brain cell degeneration, a disease marker before motor symptoms are evident.

“Of note, sEH activity can be measured in the intestines in other disease indications, suggesting its feasibility as a biomarker for Parkinson’s disease,” Borlongan said.

Therapeutic work might make use of a chemical inhibitor of sEH activity — much as the researchers did in their work, and which effectively reduced Parkinson’s-associated toxicity in both cells and animal models of the disease.

Medications that work as sEH blockers have already been tested in clinical trials for heart and lung diseases, facilitating their development as a Parkinson’s treatment, he said.

Likewise, sEH activity in stem cells collected from Parkinson’s patients was associated with the formation of alpha-synuclein aggregates, suggesting stem cell transplants could have the potential to lower sEH activity levels and prevent the accumulation of toxic alpha-synuclein toxic aggregates.

“It is conceivable that the development of sEH-based biomarkers, inhibitors, and stem cells may lead to new clinical products for inflammation-plagued disorders,” Borlongan concluded.

The post Enzyme May Be Early Biomarker of Parkinson’s and Treatment Target for Patients, Scientist Suggests appeared first on Parkinson’s News Today.

Source: Parkinson's News Today

Enzyme Tied to Inflammation and Progression in Parkinson’s May Hold Key to Treatment, Study Says

Parkinson's study

Blocking an enzyme associated with inflammation and disease progression in Parkinson’s patients may by a promising way of  treating this neurodegenerative disorder, new research suggests.

The study, “Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).

Inflammation, impaired mitochondria (the cell’s power plants) and oxidative stress are know to exist in affected brain regions of Parkinson’s patients.

Epoxy fatty acids (EpFAs) — molecules produced from the oxidation of unsaturated fatty acids — have shown potent anti-inflammatory properties in animal models. Inhibiting the enzyme that breaks down these compounds, called soluble epoxide hydrolase (sEH), further enhances their beneficial effects.

Previous research has also shown that sEH plays a key role in depressive symptoms reported in Parkinson’s patients.

Using mouse models of the disease, researchers evaluated the potential of either inhibiting or genetically deleting sEH —  specifically in the striatum, the brain region involved in Parkinson’s disease. They also investigated sEH protein levels in postmortem brain samples of patients with Lewy body dementia, a progressive dementia related to Alzheimer’s. A similar dementia can afflict Parkinson’s patients.

Repeated oral administration of TTPU — an sEH inhibitor — improved levels of dopamine, a neurotransmitter, and associated metabolites in mice.

Deleting the gene that codes for sEH also protected the brains of these mice against induced neurotoxicity, while increasing  sEH production had the opposite effect.

Higher sEH activity was observed in the brains of mice models of Parkinson’s, specifically in the striatum, and levels of this enzyme positively correlated with those of a specific form of the protein alpha-synuclein, which is the main component of Lewy bodies in Parkinson’s and the dementia patients.

In both Parkinson’s mice and the dementia patients, sEH levels in the striatum were higher than in healthy controls.

The team next tested pluripotent stem cells — able to generate almost any cell type — derived from a patient carrying PARK2, one of the familial forms of Parkinson’s and caused by a mutation in the PRKN gene.

Treating these stem cell-derived neurons with TPPU prevented the loss of domaninergic cells. Levels of sEH messenger RNA, which contains the genetic information to produce the sEH protein, were also seen to be higher in the patient stem cell-derived neurons than in healthy controls.

“Collectively, these findings suggest that sEH plays a key role in the pathogenesis of [Parkinson’s] and that sEH inhibitors may prove to be promising prophylactic or therapeutic drugs,” the researchers wrote.

They added that, although the findings in the familial Parkinson’s case warrant additional studies in other familial or sporadic patients, transplanted human stem cells may be a promising way of better understanding disease mechanisms and its treatment.

The post Enzyme Tied to Inflammation and Progression in Parkinson’s May Hold Key to Treatment, Study Says appeared first on Parkinson’s News Today.

Source: Parkinson's News Today