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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Inflammation-related Protein Complex a Potential Therapy Target for Parkinson’s, Study Says

protein complex

Oral administration of a small molecule specifically blocked the activation of a stress-sensing protein complex called the NLRP3 inflammasome and prevented the loss of brain cells, resulting in significantly improved motor function in a mouse model of Parkinson’s disease, a study reports.

Findings also revealed that the inflammasome is activated in Parkinson’s patients.

“We have used this discovery to develop improved drug candidates and hope to carry out human clinical trials in 2020,” Trent Woodruff, PhD, the study’s senior author, said in a press release.

The study, “Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice,” appeared in the journal Science Translational Medicine.

Parkinson’s is characterized by the progressive loss of dopamine-producing neurons in an area of the brain called the substantia nigra, leading to the characteristic motor symptoms. Dysfunction of the mitochondria, which provide energy to cells, accumulation of protein clumps primarily containing fibrils of alpha-synuclein, and neuroinflammation are other well-known alterations occurring in the brains of Parkinson’s patients.

The inflammasome is a multiprotein complex responsible for the activation of inflammatory responses that works as a sensor of environmental and cellular stress. Work in Alzheimer’s disease has shown that the accumulation of protein clumps can activate inflammasomes, driving inflammation in the central nervous system (CNS), which consists of the brain and spinal cord.

Using postmortem brains from Parkinson’s patients and mouse models of the disease, researchers from The University of Queensland in Australia showed that both fibrils of alpha-synuclein and loss of dopamine-producing neurons triggered the activation of the NLRP3 inflammasome in microglia — a type of cell that plays a crucial role in the CNS during immune responses to infection or injury.

“We found a key immune system target, called the NLRP3 inflammasome, lights up in Parkinson’s patients, with signals found in the brain and even in the blood,” said Woodruff, who is an associate professor in the faculty of medicine at Queensland.

An activated NLRP3 inflammasome was associated with the release of the pro-inflammatory molecule interleukin (IL)-1beta and ASC protein, which is also involved in the inflammatory response, in mouse cells, along with increased levels of activated caspase-1 — an enzyme responsible for the generation of active IL-1beta — in the substantia nigra of Parkinson’s patients.

The team found that low doses of MCC950, a small-molecule inhibitor of NLRP3, completely suppressed inflammasome activation in mouse microglia as well as ASC protein release. Importantly, once-daily, oral administration of MCC950 inhibited inflammasome activation, alpha-synuclein clumping, and loss of dopamine-producing neurons in a mouse model of Parkinson’s disease, while also easing their motor deficits.

“These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for [Parkinson’s],” the researchers wrote in the study.

Targeting microglia would represent a different strategy to that currently used by pharmaceutical companies, which have attempted to treat neurodegenerative disorders by blocking neurotoxic proteins that accumulate in the brain, said Matthew A. Cooper, PhD, one of the study’s authors and a researcher at the UQ Institute for Molecular Bioscience.

He also said that overactivation of the immune system, as well as brain inflammation and damage caused by microglia, can occur in Parkinson’s and other age-related diseases. “MCC950 effectively ‘cooled the brains on fire’, turning down microglial inflammatory activity, and allowing neurons to function normally,” he said.

“The findings provide exciting new insight into how the spread of toxic proteins occurs in Parkinson’s disease and highlights the important role of the immune system in this process,” said Richard Gordon, PhD, the study’s first author and an advance Queensland research fellow.

Gordon added that the team is now exploring approaches such as repurposing medications to target processes implicated in inflammasome-mediated disease progression.

The study was funded by The Michael J. Fox Foundation for Parkinson’s Research and Shake it Up Australia Foundation.

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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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Study Reveals Alpha-synuclein’s Role in Parkinson’s, Lewy Body Dementia

Alpha-synuclein, Parkinson's

Alpha-synuclein (aSyn), a protein linked to Parkinson’s disease and dementia with Lewy bodies (DLB), exerts its harmful effects by disrupting the normal function of protein production, a study has found.

This sheds light on the involvement of the aSyn protein in Parkinson’s disease, confirming its potential as a therapeutic target.

The study, “Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function,” was published in the journal Neurobiology of Disease.

Alpha-synuclein plays a key role in both Parkinson’s disease and DLB. This protein is the major component of Lewy bodies — protein clumps that develop inside nerve cells and contribute to neurodegeneration.

Mutations in the gene that provides instructions for making aSyn protein, the SNCA gene, are linked to familial forms of Parkinson’s disease. This is especially true for a mutation known as A30P.

Numerous neurodegenerative diseases, including Parkinson’s, are thought to be triggered by dysfunctions in the endoplasmic reticulum and Golgi complex.

These cellular structures work together and function as the body’s “postal service” by targeting and “packaging” newly produced proteins. They make sure these are delivered to their proper destination.

To understand the impact of the A30P mutation on aSyn production and on other cell functions and structures, including the endoplasmic reticulum and Golgi complex, an international team of researchers used a mouse that harbored the A30P mutation in the SNCA gene.

This allowed researchers to compare the expression of several genes in this mouse with another one that produced the healthy version of the aSyn protein. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Researchers found that the transcription — the first step in protein production (DNA to RNA) —  of several genes was deregulated in the mouse that had the A30P mutation.

In particular, the COL4A2 gene, which codes for collagen — a protein that gives form to some tissues, including the skin — was highly expressed in the A30P mouse model.

This trend was confirmed in human nerve cells that also carried the A30P mutation. Collagen is present in several membranes within the body, including the blood brain barrier, a semipermeable membrane that protects the brain from outside factors.

This overexpression was associated with lower levels of a particular molecule, called a micro-RNA, that specifically regulates and controls levels of the COL4A2 gene. These results suggest a crucial role for collagen-related genes and dysfunction in basement membranes such as the blood brain barrier in aSyn toxicity.

In human nerve cells, mutated aSyn also altered the structure of the Golgi complex and made the endoplasmic reticulum more vulnerable to stress conditions. Several studies have implicated endoplasmic reticulum stress in the development of neurodegenerative diseases.

The researchers said that he findings provide new insights “into the putative role of aSyn on transcriptional deregulation, thereby uncovering novel targets for therapeutic intervention in [Parkinson’s] and other synucleinopathies.”

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Source: Parkinson's News Today