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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