Changes in Fatty Acid Metabolism May be Linked to Parkinson’s Severity, Rat Study Finds

fatty acid metabolism

The metabolism of certain types of fats, namely palmitic acid and stearic acid commonly found in animal and vegetable fats and oils, may be altered in Parkinson’s disease, according to a study in rats.

The study, “Palmitate and Stearate are Increased in the Plasma in a 6-OHDA Model of Parkinson’s Disease,” was published in the journal Metabolites.

Studying small molecules produced by metabolism — commonly known as metabolites — within cells, biofluids, tissues, or organisms holds promise for the discovery of potential diagnostic biomarkers, which may shed light on susceptibility to Parkinson’s, disease prognosis, and therapeutic response to treatment.

In fact, an increase in metabolites of fatty acid-related molecular pathways has been reported in the plasma and cerebrospinal fluid of Parkinson’s patients, which correlated with disease progression. An increase in amino acid (protein’s building blocks) metabolism in urine samples of Parkinson’s patients has also been reported.

Evidence also suggests that metabolic profiling of cerebrospinal fluid is useful for distinguishing between newly diagnosed Parkinson’s patients and healthy individuals.

Although studies indicate that an array of molecular changes have the potential to become disease biomarkers, there is still no consensus on which markers are more informative from a diagnostic, prognostic, or even therapeutic point of view.

King’s College London researchers set out to investigate changes in brain, plasma, and liver metabolism of a rat model of Parkinson’s to discover small molecules that are associated with dopaminergic cell loss — a hallmark of the disease.

Thirteen rats were injected on one side of the brain only (unilaterally) with 6-hydroxydopamine (6-OHDA), a neurotoxin that causes the death of dopamine-producing (dopaminergic) neurons. Another 13 animals were injected with saline into the same brain region and used as a control sample.

Two weeks after injection, the animals were given two behavioral tests for researchers to assess their motor function.

“Unilateral lesions of 6-OHDA successfully resulted in the manifestation of motor symptoms, as observed by [behavioral tests] indicating the intensity of the lesions,” the researchers wrote.

Tissue analysis of the animals’ substantia nigra — a midbrain area important for muscle control that is commonly damaged in Parkinson’s disease — revealed that rats injected with 6-OHDA only had 28% of dopaminergic neurons on the injection side, compared with the other side that was not injected. Control samples had similar dopaminergic neuronal cell count on both brain sides.

Scientists then performed a metabolic analysis on the animals’ plasma, midbrain, cerebellum, and liver samples.

Results showed significantly high plasma levels of palmitic acid and stearic acid, both saturated fatty acids, within the Parkinson’s disease modeling group, which were found to be associated with motor dysfunction.

Lipid metabolism involves the degradation of triglycerides, a type of fat, into smaller chain fatty acids and subsequently into monoglycerides (glycerol molecule combined with a fatty acid) by specific enzymes.

Monoglyceride forms of palmitic acid and stearic acid, also known as monopalmitin and monostearin, respectively, were reduced in the midbrain of animals injected with 6-OHDA. Low levels of myo-inositol, a sugar alcohol molecule that has been used to decrease hormonal changes in polycystic ovary syndrome, were also found in the midbrain.

Compared with the control group, 6-OHDA rats showed a tendency toward lower levels of monopalmitin, monostearin, and myo-inositol in the cerebellum, but statistical significance was not reached.

No fatty acid-related molecular changes were observed in the animals’ livers.

“Our results show that saturated free fatty acids, their monoglycerides and myo-inositol metabolism in the midbrain and enteric circulation are associated with 6-OHDA-induced [Parkinson’s disease] pathology,” the researchers wrote.

“Changes of the midbrain metabolites may be associated with neuronal loss elicited by 6-OHDA while palmitic acid and stearic acid showed a high correlation with behaviour tests, indicating a possible association with disease severity,” they said.

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Targeting Enzyme Has Potential as Parkinson’s Therapy, Yumanity Announces

targeting enzyme

Blocking a key enzyme responsible for the production of a type of fat can become a potential therapeutic approach to treat Parkinson’s disease, Yumanity Therapeutics recently announced.

The company revealed that inhibiting an enzyme called stearoyl-CoA desaturase can protect human neurons from alpha-synuclein-derived toxicity and improve their survival.

Based on these promising results, the company plans to initiate the first-in-human clinical trial of its most advanced experimental therapy, YTX-7739, in the fourth quarter of 2019.

The findings were reported in the study, “Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity” published in the journal Cell Reports.

Previous research had found that certain fat molecules, called unsaturated fatty acids, are important mediators of the neurotoxicity caused by the protein alpha-synuclein — a key constituent of Lewy bodies, protein clumps that are a hallmark of Parkinson’s disease.

Importantly, in cell and animal models of the disease, inhibiting the enzyme stearoyl-CoA-desaturase (SCD), key for the production of unsaturated fatty acids (specifically palmitoleic and oleic), could protect against the formation of alpha-synuclein aggregates and its related toxicity.

Using Yumanity’s drug discovery platform, researchers screened for compounds that could protect against alpha-synuclein-induced toxicity. They found a series of small molecules — including YTX-7739 — that was able to rescue yeast cells from the cellular defects and growth impairments caused by alpha-synuclein. YTX-7739 worked by blocking SCD, further supporting the enzyme as a potential therapeutic target for Parkinson’s.

SCD is the first potential target identified by Yumanity’s discovery engine, a group of screening platforms based on yeast and human neurons aimed at finding new and druggable targets for difficult-to-treat, protein misfolding-related neurodegenerative diseases including Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS).

The team confirmed its hypothesis in a laboratory model of human neurons derived from pluripotent stem cell (iPCS). iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of any type of human cell needed for therapeutic purposes.

When these model neurons were treated with a commercially available inhibitor of SCD, the neurodegenerative effects of alpha-synuclein were reduced and the cells lived longer. As expected, this protective effect was linked to a decrease in the levels of unsaturated fats inside neurons.

Even though it seems like a promising therapeutic approach to explore, its “precise mechanism of protection is not entirely defined” researchers wrote.

Fatty acids, and oleic acid in specific, are crucial components of cell membranes — both the plasma membrane, which separates the interior of cells from the outside environment, and membranes that enclose crucial structures within the cell.

Based on this knowledge and the study’s results, researchers propose three possible mechanisms for the protective effects of blocking SCD: a toxic increase in fatty acid desaturation is directly reversed by SCD inhibition; reduced fatty acid desaturation (a consequence of blocking SCD) reverses the toxic effects of alpha-synuclein on membrane properties or transport processes within the cell (cellular trafficking); or the reduced fatty acid desaturation enhances a direct toxic interaction of alpha-synuclein with cell membranes.

“The lack of effective new disease-modifying treatments for these disorders stems largely from a scarcity of novel drug targets, and a poor understanding of disease biology,” Ken Rhodes, PhD, chief scientific officer of Yumanity Therapeutics and senior author of the study, said in a press release.

“These new findings are important because they pinpoint a novel mechanism underlying alpha-synuclein toxicity and offer a potential new therapeutic approach to treating Parkinson’s disease through the inhibition of SCD activity,” he said.

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Enzyme Linking Fatty Acids to Alpha-synuclein Could Be Parkinson’s Therapeutic Target, Study Suggests

alpha-synuclein, fatty acids

Inhibiting an enzyme that regulates the production of fatty acids may protect against brain toxicity induced by alpha-synuclein in Parkinson’s disease and may become a therapeutic target for these patients, a study reports.

The study, “Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment,” was published in the journal Molecular Cell.

The brain is rich in lipids, or fats, which are key for neural development and nerve cell communication. Brain cells tightly regulate lipid production and uptake, as well as the distribution of its precursors, such as fatty acids. Imbalance of the brain’s lipids has been implicated in several neurodegenerative diseases, including Parkinson’s.

Alpha-synuclein, the main component of protein clumps known as Lewy bodies, interacts with fatty acids and favors their storage as triglycerides — the most common type of fat in the body — in lipid droplets in cells.

These droplets prevent the toxic effects of lipid accumulation, but may also contribute to the deposition of alpha-synuclein. Proteins related to lipid metabolism have been identified as risk factors for Parkinson’s. However, little is known about the impact of lipid metabolism on alpha-synuclein assembly and cellular alterations.

Researchers first measured lipids and fatty acid alterations in yeast that had been engineered to produce alpha-synuclein. This showed an increase in components of the neutral lipids pathway — storage lipids lacking positively and/or negatively charged groups — including a monounsaturated fatty acid called oleic acid. The team thereby hypothesized that high oleic acid levels promote the binding of alpha-synuclein to the cell membrane, increasing toxicity.

These findings were then replicated in patient cell lines, in a mouse model of familial Parkinson’s, and in a model of dopamine-producing neuron degeneration (a hallmark of Parkinson’s) in the nematode worm Caenorhabditis elegans.

“It was fascinating to see how excess [alpha-synuclein] had such consistent effects on the neutral lipid pathway across model organisms,” Ulf Dettmer, PhD, co-senior author of the study from the Brigham and Women’s Hospital and Harvard Medical School, said in a press release. “All our models clearly pointed at oleic acid as a mediator of [alpha]-synuclein toxicity.”

Researchers investigated possible ways to target fatty acids or the processes leading to their production that could protect against Parkinson’s. They found that triglycerides protect from alpha-synuclein-induced toxicity by preventing the accumulation of oleic acid and diglyceride, a type of fat composed of two fatty acid chains.

Importantly, they found that inhibiting an enzyme known as stearoyl-CoA-desaturase (SCD), which is key in the production of oleic acid, protected against cell toxicity, formation of alpha-synuclein aggregates, and a decrease in the amount of protective alpha-synuclein tetramers (natural structure formed by four subunits) relative to its aggregation-prone monomers, or single-protein chains.

“Our findings thus indicate that partial inhibition of SCD would be a rational therapeutic approach to [alpha-synuclein] neurotoxicity,” the researchers wrote.

“We’ve identified a pathway and a therapeutic target that no one has pursued before,” said Saranna Fanning, PhD, the study’s lead author.

Co-senior author Dennis Selkoe, MD, said the findings present “a unique opportunity for small-molecule therapies to inhibit the enzyme in models of [Parkinson’s] and, ultimately, in human diseases.”

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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.

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Source: Parkinson's News Today