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Potential Treatment to Prevent Toxic Protein Clumping Enters Phase 1 Trial, Yumanity Announces

YTX-773 Phase 1 trial

Yumanity Therapeutics announced the start of a Phase 1 clinical study in healthy volunteers that will assess the safety and tolerability of YTX-7739, a potential disease-modifying therapy for Parkinson’s disease.

Trial results are expected to be announced in the first quarter of 2020.

YTX-7739 is designed to cross the blood-brain-barrier — a semipermeable membrane that protects the brain and spinal cord from the external environment — to inhibit the activity in the brain of an enzyme called stearoyl-CoA desaturase (SCD) .

This enzyme is known to play a key role in the production of certain fat molecules, called unsaturated fatty acids, that mediate the neurotoxic effects of alpha-synuclein protein accumulation — a key constituent of Lewy bodies, the toxic protein clumps that are a Parkinson’s hallmark.

In cell and animal disease models, the investigational medicine was shown to protect neurons against alpha-synuclein-derived toxicity and improve their survival.

“We advanced YTX-7739, an orally-active SCD inhibitor, into clinical development because of recent evidence established at Yumanity Therapeutics demonstrating its promise to protect cells from a-synuclein toxicity,” said Kenneth Rhodes, PhD, the company’s chief scientific officer, said in a press release.

“We look forward to fully characterizing the potential clinical use of YTX-7739, which is clearly differentiated from currently available Parkinson’s disease therapies that only address the symptoms, not the underlying causes.”

The Phase 1 trial is expected to enroll about 40 healthy volunteers, who will be randomly assigned to increasing doses of oral YTX-7739 or dose-matching oral placebo. Collected data will assess YTX-7739’s safety and tolerability, as well as its stability and metabolization (pharmacokinetics) inside the body: essentially, how the body affects a medicine.

If results are promising, Yumanity plans to advance YTX-7739 into a Phase 1b proof-of-concept clinical trial in patients, possibly in the second half of 2020.

“This Phase 1 trial will provide important validation for the broad application of our technology to help address arguably the most important therapeutic challenges of our time,” like that of “protect[ing] cells from neurodegeneration,” said Richard Peters, MD, PhD, Yumanity’s CEO.

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Lewy Bodies Diverse in Structure and Some Fibrils Can Migrate, Study Reports

alpha-synuclein study

A detailed analysis of the structure of alpha-synuclein clumps suggests that Parkinson’s is a systemic disease, whose characteristic protein aggregates can move about inside the brain and migrate beyond the central nervous system, according to a new research.

This finding may help in better understanding why Parkinson’s patients experience symptoms other than the disease’s characteristic motor problems.

The study, “Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein,” was published in the journal Proceedings of the National Academy of Sciences.

A hallmark feature of Parkinson’s is the accumulation of small and complex structures called Lewy bodies, which are mainly composed of the alpha-synuclein protein in nerve cells of the brain. Recent work has shown these aggregates can travel across cells of connected brain regions. But little is known about how this migration is regulated, and scientists are still working to more fully understand the structure of proteins in Lewy bodies.

A team from Osaka University, in Japan, used a technique called microbeam X-ray diffraction to gather information in greater detail about the structure of alpha-synuclein clumps.

Using this technique, researchers can detail the complex 3D structure of protein aggregates based on the diffraction pattern they produce when crossing a beam of X-rays. (Diffraction patterns here refer to the bending of X-ray waves as they pass an object.)

The team first tested the sensitivity of their approach using senile plaques from mice in a model of Alzheimer’s disease. These plaques are also composed of complex protein clump, but consist of the beta-amyloid protein.  The researchers then used the same method to analyze thin brain sections taken from three Parkinson’s patients who died between the ages of 75 and 83.

Tests confirmed that protein clumps from patients mainly consisted of alpha-synuclein, by using an antibody specific for detecting this protein. Next, the researchers saw different X-ray scattering patterns in mice and patient tissue samples, confirming they consisted of different proteins.

They also found that different patient samples had slightly different scattering patterns, suggesting diverse clump structures. Importantly, some structures seen in patients’ alpha-synuclein aggregates were similar to structures previously reported in mice studies, which found fragments of these protein fibrils (called cross-beta, or cross-β, structures) could propagate — migrate — throughout the body.

“Our study is the first to find that aggregates in Parkinson’s disease brains also have this cross-β structure,” Hideki Mochizuki, MD, PhD, the study’s senior author, said in a news release.

Inconsistent findings across patient samples might indicate “the different maturity stages of Lewy bodies,” said Katsuya Araki, MD, PhD, and the study’s first author.

Importantly, rather than supporting Parkinson’s as a disease localized in the brain, “our finding supports the concept that [Parkinson’s] is a type of amyloidosis, a disease featuring the accumulation and propagation of amyloid fibrils” of alpha-synuclein, they wrote.

This appears to be in line with both the non-motor symptoms experienced by Parkinson’s patients before difficulties with movement are manifest, and with the presence of alpha-synuclein deposits found in peripheral nerves of the heart and the gut.

“This has obvious implications in the diagnosis of Parkinson’s disease, and could also have therapeutic implications in the long run,” Araki said.

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Alpha-Synuclein Protein Works to Repair Damage to Cell’s DNA, Study Suggests

alpha-synuclein and DNA repair

Contrary to current knowledge, alpha-synuclein protein — whose toxic form is responsible for the formation of Lewy bodies — may play a crucial role in preventing cell death by repairing damaged DNA, a study has found.

This critical function of the protein may also be lost in Parkinson’s patients, its researchers said.

The study, “Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders,” was published in Scientific Reports.

Parkinson’s is marked by a buildup in the brain of the alpha-synuclein protein, which forms clumps known as Lewy bodies that damage and kill neurons (nerve cells). These protein inclusions are found in the cell’s cytoplasm — the jelly-like fluid that fills a cell.

Although it remains unclear how cytoplasmic aggregation of alpha-synuclein into Lewy bodies contributes to neuronal death, alpha-synuclein has also been found in the cell’s nucleus, where DNA is located and where important DNA repair mechanisms take place.

Researchers at the Oregon Health & Science University had previously shown that the formation of Lewy bodies coincided with the loss of soluble alpha-synuclein from both the cytoplasm and nucleus of mouse neurons with aggregates (clumps) in them.

“This suggests that cytoplasmic alpha-synuclein aggregation may decrease the amount of protein available for any nuclear or cytoplasmic role it may play,” the researchers wrote.

The same team now investigated whether alpha-synuclein could be involved in the DNA damage response.

Alpha-synuclein was found in the same cellular sites as DNA damage response components in both human and mouse brain cells.

DNA damage was then chemically induced in human cells that lacked alpha-synuclein. Researchers reported finding higher rates of DNA damage (what they called “double-strand breaks”) compared to alpha-synuclein-bearing cells. Likewise, mice without alpha-synuclein had increased neuronal DNA damage, which was rescued by reintroducing the human form of alpha-synuclein.

Importantly, mouse and human neurons with Lewy bodies had increased levels of DNA damage.

Scientists also observed that normal (i.e., non-toxic) alpha-synuclein is rapidly recruited to DNA damage sites and helps to repair harm by binding to the DNA molecule and facilitating a repairing reaction; more specifically, this process is called the non-homologous end-joining reaction.

Besides its known toxic role in Parkinson’s, findings suggest alpha-synuclein may have an important function in the cell nucleus, that of regulating DNA repair. They also suggest that such function is compromised in Lewy inclusion-bearing neurons, which, in turn, contributes to cell death.

“This is the first time that anyone has discovered one of its [alpha-synuclein’s] functions is DNA repair,” Vivek Unni, MD, PhD, an associate professor of neurology in the OHSU School of Medicine and senior author of the study, said in a news release.

“That’s critical for cell survival, and it appears to be a function that’s lost in Parkinson’s disease,” Unni added.

“Based on these data, we propose a model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs [double-strand breaks], and may contribute to programmed cell death via nuclear loss-of-function. This model could inform development of new treatments for Lewy body disorders by targeting alpha-synuclein-mediated DNA repair mechanisms,” the team concluded.

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Lewy Bodies Are Made of Much More than Alpha-Synuclein, Study Finds

Lewy bodies

Insoluble alpha-synuclein protein has long been thought to be the main component of Parkinson’s hallmark Lewy bodies, but researchers have now reported these abnormal aggregates are also made of cell membrane fragments, fat-like substances, and other cellular components.

This finding was reported in a study, “Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes,” that was published in the journal Nature Neuroscience.

Parkinson’s disease is a neurodegenerative disorder characterized by selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies.

For decades, scientists have believed that alpha-synuclein fibrils (meaning “small fibers”) were the main component of and at Lewy bodies’ core. However, investigators have now contested such belief after studying postmortem human brain tissue from patients with Parkinson’s disease.

Combining imaging techniques, the researchers were able to re-create the 3D structures of these disease-associated clusters. They found that besides alpha-synuclein, Lewy bodies also have membrane fragments, vesicular structures, and abnormal organelles (organ-like structures found inside cells) such as mitochondria — cells’ powerhouses.

Many, but not all, Lewy bodies with alpha-synuclein within them had protein fibers scattered between membrane fragments and organelles. Importantly, a non-fibrillar form of alpha-synuclein was also found to be intermingled with the other contents of the Lewy bodies.

“We used correlative light and electron microscopy and other advanced light microscopy methods to take a closer look at the brain of deceased Parkinson’s patients and discovered that the Lewy bodies consist mainly of membrane fragments from mitochondria and other organelles, but have in most cases no or only negligible quantities of protein fibrils,” Henning Stahlberg, PhD, professor and researcher at the University of Basel in Switzerland, and one of the study’s senior authors, said in a press release.

“The discovery that alpha-synuclein did not present in the form of fibrils was unexpected for us and the entire research field,” Stahlberg said.

The researchers also found that the bodies carried fat-like substances similar to those found in healthy brain cells, like myelin (nerve cells’ protective fatty layer) or fatty components of cell membranes.

“We present here a new theoretical model in which lipid membrane fragments and distorted organelles together with a non-fibrillar form of [alpha-synuclein] are the main structural building blocks for the formation of Lewy pathology,” the researchers stated.

Several studies have linked disturbances in intracellular movement of molecules and organelles with Parkinson’s disease. In addition, alpha-synuclein has been shown to be capable of disrupting the integrity of mitochondrial membranes, manipulating and reorganizing membrane components, and leading membranes to form vesicles under specific biochemical conditions.

Collectively, the study’s findings support the hypothesis of abnormal movement of organelles as a potential driver of Parkinson’s disease mechanism. Also, they “emphasize the need to consider population heterogeneity of Lewy pathology” and show that lipids (cells’ fatty molecules) could play an important role, the researchers said.

“The questions why it has taken so long to better characterize Lewy bodies can perhaps be answered with the previous sample preparation and electron microscopy methods. Today’s technologies enable us to have a much more detailed look into the morphology of [the] human brain,” Stahlberg said. “The big question for us now is: How does alpha-synuclein contribute to the formation of Lewy bodies, if not present in [the] form of fibrils?”

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Gut Alpha-Synuclein May Be Used as Biomarker of Parkinson’s, Study Suggests

Gut alpha-synuclein

Alpha-synuclein levels in the gut are linked to Parkinson’s disease, indicating that gut alpha-synuclein may be used in combination with other disease biomarkers to facilitate patients’ diagnosis, a review study found.

The study, “Diagnostic utility of gut α-synuclein in Parkinson’s disease: A systematic review and meta-analysis,” was published in Behavioural Brain Research.

Parkinson’s disease is associated with the overproduction of the protein alpha-synuclein in nerve cells of the brain. When this protein clumps together, it gives rise to small toxic deposits inside brain cells, called Lewy bodies.

Alpha-synuclein phosphorylation — a chemical modification in which a phosphate group is added to the protein — is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression as it enhances alpha-synuclein’s toxicity, possibly by increasing the formation of alpha-synuclein aggregates.

Some scientists think Lewy bodies form in the enteric nervous system (ENS) — the network of nerves that innervate the gastrointestinal tract — then spread to the brain, where they will gradually damage and destroy brain cells.

Although alpha-synuclein has already been detected in tissue samples collected from the stomachs and colons of Parkinson’s patients, its usefulness as a disease biomarker is still controversial.

Chinese researchers conducted a systematic review focused on assessing the relationship between gut alpha-synuclein and Parkinson’s, as well as its diagnostic power in distinguishing patients with the disease from those without it (controls). They reviewed 21 previously published studies reporting findings on gut alpha-synuclein, or phosphorylated alpha-synuclein.

Pooled data from the studies revealed that patients with Parkinson’s were approximately 10 times more likely to have deposits of alpha-synuclein in the gut compared to control subjects. This suggests a direct relationship between gut alpha-synuclein and Parkinson’s disease.

Further analysis showed that gut alpha-synuclein and phosphorylated alpha-synuclein could correctly identify 81.9% and 82.2% of individuals who did not have Parkinson’s disease. However, both had poor sensitivity and failed to distinguish patients with the disease from control subjects in approximately half the cases — a sensitivity of 56.8% for gut alpha-synuclein and 57.9% for phosphorylated alpha-synuclein.

“These results showed that a single measurement of gut [alpha]-synuclein could lead to the underdiagnosis of Parkinson’s disease,” researchers said. “This systematic review and meta-analysis confirmed a high degree of association between gut α-synuclein and Parkinson’s, which suggested that gut [alpha]-synuclein is a potential therapeutic intervention.”

Additional studies are still warranted to further explore the diagnostic potential of gut alpha-synuclein when combined with other biochemical markers of the disease, and “more efforts should be made to improve the standardization of current assays,” they said.

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Engineered Stem Cells Could Be Next Parkinson’s Treatment, Researchers Say

gene editing

Cutting out a portion of or removing a gene linked to Parkinson’s disease protects against the formation of toxic protein clumps within brain cells, scientists have found.

This discovery has the potential to significantly affect the development of next-generation cell-based therapies, which involve injecting healthy cells into brain regions already affected by the disease. Researchers believe the approach may help relieve motor symptoms such as tremor and balance issues.

Findings were published in the study, “Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene,” in the European Journal of Neuroscience. The work was funded by the U.K. Centre for Mammalian Synthetic Biology, UCB, and The Cure Parkinson’s Trust.

Mutations in the SNCA gene have been found to cause Parkinson’s, a condition characterized by the selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein, also known as Lewy bodies.

Transplantation of dopamine-producing neurons has proved useful in disease management because it can reinnervate Parkinson’s-affected brain regions, restore dopamine levels, and provide symptom relief.

Clinical studies on the transplant of fetal mesencephalic (meaning “of or relating to the midbrain”) tissue into the striatum — a critical area of the brain involved in Parkinson’s — have shown that although some patients saw their motor symptoms improved, others had transplant-induced dyskinesias — abnormal, uncontrolled, and involuntary movement.

Importantly, transplanted tissue (grafts) older than 10 years developed Lewy bodies, which reduced the symptomatic benefit to the patient.

“These clinical observations highlight the need for cell therapies that are resistant to the formation of Lewy bodies. … Such disease-resistant cells will be particularly important for patients with young-onset Parkinson’s or genetic forms of the condition with substantial alpha-synuclein burden,” the researchers wrote.

The team used a gene editing tool known as CRISPR-Cas9. This technique allows scientists to edit parts of the genome by removing, adding, or altering specific sections of the DNA sequence.

Using stem cells, researchers created two distinct cell lines: one with snipped-out portions of the SNCA gene and another without the SNCA gene.

These stem cells were then transformed into dopamine-producing neurons and treated with a chemical agent (recombinant alpha-synuclein pre-formed fibrils) to induce the formation of Parkinson’s-related Lewy bodies.

The team reported that wild-type neurons, or unedited brain cells, were fully susceptible to the formation of toxic aggregates, while engineered cells were significantly resistant to Lewy body formation.

“We know that Parkinson’s disease spreads from neuron [to] neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments,” Tilo Kunath, PhD, group leader at the Medical Research Council’s Centre for Regenerative Medicine, University of Edinburgh, and senior author of the study, said in a press release.

By finding a way to “shield” cells from Parkinson’s molecular changes, scientists may have opened the door to the development of cell therapies capable of diverting time’s negative effect on transplanted tissue.

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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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Other Things Lewy Bodies Might Do to Our Brains

Lewy bodies

Editor’s note: This column discusses suicide.

Pivotal events in my life have piqued my interest in Lewy bodies. The first event was on March 15, 2015, when my life partner, Steve, killed himself. The second was my diagnosis of Parkinson’s disease in November 2015.

My fascination with Lewy bodies (I’ll define them in a bit) began in August 2016 when I watched a documentary called “Autopsy: The Last Hours of Robin Williams.” In this film, forensic pathologist  Richard Shepherd, MD investigated what might have driven Robin to suicide in August 2014. A few months before he died, the beloved comedian and actor had been diagnosed with Parkinson’s.

What might Steve and Robin have in common?

Both Steve and Robin suffered from depression, yet both were supremely talented men with the ability to make so many people happy. To many, it appeared as if they both had lives full of promise ahead of them. According to the documentary, Robin was at a crossroads in his career. Steve also was at a crossroads in his life, trying to sell the business he had built and grown for more than 20 years. The film implied that Robin may have turned to drugs and alcohol to feel better and mask his depression. I believe Steve turned to endurance sports much of his life to accomplish the same. Steve was an 18-time Ironman triathlete finisher, which entails 2.4 miles of swimming, 112 miles of cycling, and 26.2 miles of running.

In my mind, their lives and tragic endings have so much in common.

What are Lewy bodies?

Lewy bodies are abnormal deposits of a protein called alpha-synuclein. These deposits can change how a person feels, thinks, moves, and acts. Lewy bodies can be found in an area of the brain stem where they deplete dopamine, causing Parkinson’s symptoms. There also is a disease called Lewy body dementia, in which these abnormal proteins spread to other areas of the brain. An affected person may become anxious and paranoid. Their decision-making can become impaired. Lewy body dementia can be definitively diagnosed only by a postmortem autopsy.

What was the result of Robin’s autopsy?

According to Shepherd, Robin’s autopsy confirmed the presence of Lewy bodies throughout his brain. Shepherd interviewed the Williams family in an effort to determine Robin’s state of mind prior to his suicide. Robin’s loved ones said he showed signs of paranoia. Shepherd concluded that Robin had undiagnosed Lewy body dementia and that it was this disease that drove him to take his own life.

Steve did not have an autopsy. In many states, if the cause of death is apparent, as it was with Steve, an autopsy is not automatically performed. Steve, like Robin, suffered from depression, and he spiraled downward quickly starting in 2014. A few weeks before he died, Steve expressed to me that he was afraid, but he could not, or would not, articulate why. He was my rock, my Ironman, and he never had been afraid of anything before.

I am not a medical professional, and I wrote this column to inspire conversation about undiagnosed Lewy body dementia as a possible cause of suicide, as Shepherd concluded in the case of Robin Williams.

What can we learn from Robin’s death?

I often wonder if brain autopsies should be routinely performed and analyzed for the presence of Lewy bodies in cases of suicide. Obviously, there are emotional considerations for the families and costs involved, but perhaps the knowledge learned from these autopsies may help others.

Maybe undiagnosed Lewy body dementia is more prevalent than we think, especially when suicide is the obvious cause of death.

If you or anyone you know is experiencing suicidal thoughts or needs someone to talk to, please call the National Suicide Prevention Line at 800-273-8255 or visit suicidepreventionlifeline.org.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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New Mouse Model Aids in Study of Alpha-Synuclein’s Role in Parkinson’s Disease

Parkinson's mouse model

A new transgenic Parkinson’s disease mouse model is able to recapitulate the motor symptoms and biological causes of disease, including alpha-synuclein protein aggregation, a study reports.

Similar to Parkinson’s patients, this model also responds to levodopa, one of the main compounds used to treat symptoms of the disease.

The study, “Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease,” was published in the journal Neuron.

“It is difficult to find efficient treatment therapies that target αS [alpha-synuclein] aggregation,” Silke Nuber, PhD, from the Brigham and Women’s Hospital (BWH) in Boston and the study’s first author, said in a press release. “Thus, it is necessary to develop mouse models that reflect the long-term changes, including Lewy-like aggregation of αS and an associated close PD [Parkinson’s disease]-phenotype, to better understand the mechanisms that lead to the initiation of PD.”

The brains of Parkinson’s patients are characterized by the accumulation of a protein called alpha-synuclein into clumps known as Lewy bodies. This accumulation affects nerve cells, causing them to die.

Alpha-synuclein plays a key role in a healthy brain, regulating the release of synaptic vesicles — “bubbles” filled with chemical neurotransmitters (messengers) that are released between nerve cells or between nerve cells and their effector cells, such as those in the muscle.

This regulation occurs when alpha-synuclein is in its healthy state, i.e., arranged in a tetramer — four units of the protein wrapped around each other.

In familial cases of Parkinson’s disease, patients may carry mutations in the alpha-synuclein gene that contribute to the clumping of alpha-synuclein by shifting tetramers to aggregation-prone monomers — when the natural tetramer structure is replaced by single-protein chains, or monomers.

This causes the death of dopamine producing-nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, a critical signaling molecule that regulates brain cell activity and function.

Researchers at BWH have now developed a new transgenic mouse model that carriers a mutant form of alpha-synuclein — what they call a tetramer-lowering mutation — to understand its contribution to the disease.

Specifically, researchers engineered several mouse lines carrying different alpha-synuclein mutations that impact the natural tetramer structure of the alpha-synuclein protein, mimicking what occurs in familial cases of the disease.

“With these new mice, we set out to examine the upstream role of tetramer-lowering mutations and their relevance to PD,” Nuber said. “Our hypothesis was that upstream destabilization of normal tetramers to excess monomers can lead to the changes of PD.”

They compared their newly developed mouse model with mice expressing a functional alpha-synuclein protein (wild-type mice) and with mice carrying a single mutation in the alpha-synuclein gene, typically found in familial cases of Parkinson’s disease.

Researchers evaluated the animals’ behavioral features, along with conducting molecular and tissue analysis.

The new tetramer-abrogating mouse model developed spontaneous behavioral changes typical of Parkinson’s disease, including abnormal gait and gradual worsening of head and body tremor. None of these features were detected in the wild-type healthy mice.

These motor deficits were more prominent in male mice, a phenomenon also observed in Parkinson’s patients.

The loss of alpha-synuclein tetramer structural organization led to the accumulation of the protein’s monomers that resulted in the degeneration of dopaminergic neurons in the brain cortex, specifically in a region called the substantia nigraone of the main regions affected in Parkinson’s — and triggered the progressive loss of motor function.

Importantly, just like in humans, motor deficits in these mice were improved upon treatment with Parkinson’s therapy levodopa, also called L-DOPA.

These findings suggest that the tetramer structure of alpha-synuclein is required for a healthy brain, and that loss of its structure may contribute to Parkinson’s disease onset.

“We can now examine PD in a whole new light. We can think about stabilizing the physiological αS [alpha-synuclein] tetramer, an entirely novel therapeutic concept, as a means of preventing or delaying the onset of PD,” Nuber said.

“With our lab’s experience in deciphering the earliest stages of Alzheimer’s disease, we decided some time ago to apply analogous approaches to the different protein abnormality occurring in PD,” said Dennis Selkoe, MD, the study’s lead author.

“We believe this unique mouse model shows that the tetrameric form of αS we discovered in 2011 is necessary for normal neuronal function, so that abrogating the tetramer has direct PD-like consequences. This PD mouse model will provide a new route to entirely novel therapeutic approaches,” said Selkoe, who is also the co-director of the Ann Romney Center for Neurologic Disease at BWH.

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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