Health

Hidden cellular “power switch” could transform Parkinson’s treatment

A key switch for cellular energy balance has been discovered in cells: it could potentially become the target of new therapies for diseases ranging from Parkinson's to rare disorders caused by defects in the cell's powerhouses, the mitochondria. The switch is called phosphatase B55 (PP2A-B55alpha) and regulates the balance of mitochondria. Experts from Università Cattolica, Rome campus, and Roma Tre Universty have observed that, by reducing its activity, it's possible to attenuate the motor symptoms of Parkinson's in a preclinical model of the disease.

This is the result of a study published in Science Advances, led by Francesco Cecconi, Full Professor of Biochemistry at the Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Medicine at the Università Cattolica, and conducted by Valentina Cianfanelli, Associate Professor at the Department of Science at Roma Tre University and Principal Investigator of the Young Researchers Project at the Gynecological Oncology Unit of Fondazione Policlinico Universitario Agostino Gemelli IRCCS.

Background

Mitochondria are highly complex cellular organelles, vital for cell survival. They are responsible for producing the energy cells need to survive. Their integrity is associated with several diseases, both widespread, such as Parkinson's, and rare, so-called mitochondrial diseases, which can affect various parts of the body, from muscles to eyes to the brain. Inside cells, there is a delicate balance between old or damaged mitochondria that must be eliminated and new ones that must replace them. In some diseases, however, this balance is disrupted, and if mitochondria are lost in excess, or if damaged organelles accumulate in the cell and are regularly not eliminated, the very survival of the cell is endangered.

In the case of Parkinson's disease, for example, the loss of mitochondria also plays a role in the death of dopaminergic neurons that underlies the disease.

The Study

Experts have discovered that B55 plays a key role in regulating mitochondrial homeostasis.

"On the one hand," Professor Cecconi explains, "it promotes the removal of damaged mitochondria by stimulating mitophagy, a selective process for removing inefficient and potentially dangerous organelles. On the other, B55 acts as a controller of mitochondrial biogenesis, stabilizing the main promoter of new mitochondrial formation.

In this way, B55 not only promotes the degradation of damaged mitochondria, but also prevents excessive production of new organelles, thus maintaining a dynamic balance between mitochondrial elimination and synthesis. It is of great interest," the expert emphasizes, "that both these effects depend on the functional interaction between B55 and Parkin, a central protein in mitophagy mechanisms, implicated in Parkinson's disease.

Professor Cecconi and Cianfanelli explain: it is no coincidence that in our research, using animal models of Parkinson's disease (Drosophila, the fruit flies), "we observed that by reducing B55 levels we can improve both the motor defects and the mitochondrial alterations typical of the disease." This effect requires the presence of the Parkin factor and acts primarily on mitochondrial biogenesis.

The idea could be to develop small molecules capable of penetrating the brain and selectively acting on dopaminergic neurons, counteracting their death.

More generally, a 'universal' drug that regulates the action of B55 could be developed for various mitochondrial diseases characterized by mitochondrial loss, including some mitochondrial myopathies and neurodegenerative diseases, Professor Cecconi explains. Furthermore, the deregulation of mitochondrial quality and number also underlies the plasticity of tumor cells and their ability to resist therapies, so controlling B55 could become a promising approach in oncology.

This is why "our future studies will aim to identify safe molecules and therapeutic strategies to modulate B55 in preclinical and human cellular models, especially in order to analyze the effect of its regulation on other neurodegenerative and mitochondrial diseases," they conclude.

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The vitamin D mistake weakening your immunity

Taking vitamin D2 might lower the body's levels of the more efficient form of vitamin D, vitamin D3, according to new research from the University of Surrey, John Innes Centre and Quadram Institute Bioscience. Many people take vitamin D supplements to support their bone and immune health and meet the UK government recommendation of 10 micrograms (µg) each day, especially during the winter months.

There are two forms of vitamin D supplements available: vitamin D2 and vitamin D3. Researchers have found that taking vitamin D2 supplements can lead to a drop in the body's concentration of vitamin D3, which is the form our bodies naturally produce from sunlight and use most effectively to raise overall vitamin D levels.

The study, published in Nutrition Reviews, analysed data from randomised controlled trials and found that vitamin D2 supplementation resulted in a reduction in vitamin D3 levels compared to those not taking a vitamin D2 supplement. In many of the studies, the vitamin D3 levels went lower than in the control group.

Emily Brown, PhD Research Fellow and Lead Researcher of the study from the University of Surrey's Nutrition, Exercise, Chronobiology & Sleep Discipline, said:

"Vitamin D supplements are important, especially between October and March, when our bodies cannot make vitamin D from sunlight in the UK. However, we discovered that vitamin D2 supplements can actually decrease levels of vitamin D3 in the body, which is a previously unknown effect of taking these supplements. This study suggests that subject to personal considerations, vitamin D3 supplements may be more beneficial for most individuals over vitamin D2."

Professor Cathie Martin, Group Leader at the John Innes Centre, said:

"This meta-analysis highlights the importance of ensuring plant-based vitamin D3 is accessible in the UK."

This research supports a previous study published in Frontiers in Immunology, led by Professor Colin Smith from the University of Surrey, which suggests that vitamin D2 and D3 do not have identical roles in supporting immune function. Vitamin D3 has a modifying effect on the immune system that could fortify the body against viral and bacterial diseases.

Professor Colin Smith said:

"We have shown that vitamin D3, but not vitamin D2, appears to stimulate the type I interferon signalling system in the body -- a key part of the immune system that provides a first line of defence against bacteria and viruses. Thus, a healthy vitamin D3 status may help prevent viruses and bacteria from gaining a foothold in the body."

Further research into the different functionalities of vitamin D2 and D3 should be a priority in deciding whether vitamin D3 should be the first-line choice of vitamin D supplement, subject to individual requirements.

Professor Martin Warren, Chief Scientific Officer at the Quadram Institute, said:

"Vitamin D deficiency represents a significant public health concern, especially during the winter months with significant deficiency across the UK population. This collaborative research effort aligns well with the Quadram Institute's mission to deliver healthier lives through food innovation to enhance the nutrient density of the food we eat. Tackling this with the most effective form of vitamin D supplementation or fortification is of the utmost importance to the health of the nation."

This “chaos enzyme” may hold the key to stopping cancer spread

Triple negative breast cancer (TNBC) is one of the most aggressive and hardest forms of breast cancer to treat, but a new study led by Weill Cornell Medicine suggests a surprising way to stop it from spreading. Researchers have discovered that an enzyme called EZH2 drives TNBC cells to divide abnormally, which enables them to relocate to distant organs. The preclinical study also found drugs that block EZH2 could restore order to dividing cells and thwart the spread of TNBC cells.

"Metastasis is the main reason patients with triple negative breast cancer face poor survival odds," said senior author Dr. Vivek Mittal, Ford-Isom Research Professor of Cardiothoracic Surgery and member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "Our study suggests a new therapeutic approach to block metastasis before it starts and help patients overcome this deadly cancer."

The findings, published Oct. 2 in Cancer Discovery, challenge the popular notion that cancer treatments should boost cell division errors already occurring in tumor cells beyond the breaking point to induce cell death. When normal cells divide, the chromosomes -- DNA "packages" carrying genes -- are duplicated and split evenly into two daughter cells. This process goes haywire in many cancer cells, leading to chromosomal instability: too many, too few, or jumbled chromosomes in multiple daughter cells.

"I find the attempt to drive cancer cells over the edge with more chromosomal instability a little concerning because if you don't reach the right level, it may paradoxically lead to aggressive disease," Dr. Mittal said. "Instead, our findings suggest that restoring order to cell division by targeting EZH2 can stop them from spreading."

First author Dr. Shelley Yang Bai began this work as a graduate student and is now a postdoctoral associate with Dr. Mittal in cardiothoracic surgery at Weill Cornell Medicine. Dr. Samuel Bakhoum, who was at Memorial Sloan Kettering Cancer Center at the time, co-led this study.

Linking Epigenetics and Metastasis

About 5% of cells in a TNBC primary tumor are highly likely to metastasize, and these cells have unique features such as different metabolism, increased chromosomal instability and altered epigenetics -- modifications to DNA or its associated proteins that do not directly change the genetic code.

Dr. Mittal's team found a suspicious culprit that could be triggering metastasis in these particular cancer cells: EZH2. This protein normally modifies how DNA is packaged in cells. But cancers often hijack EZH2 by increasing its production. In TNBC, this overproduction leads to the silencing of key genes needed for chromosomes to segregate properly during cell division and to rampant errors.

When analyzing data from breast cancer patients, Dr. Bai found that patients with higher levels of EZH2 also had tumor cells with more chromosomal alterations. This provided clues for further lab experiments. While inhibiting EZH2 with tazemetostat, an FDA-approved drug to treat certain cancers, reduced chromosomal instability in cell lines, boosting EZH2 levels genetically increased errors in cell division.

Furthermore, mouse models with elevated EZH2 and chromosomal instability in primary tumors showed increased lung metastases compared to tumors lacking EZH2, confirming a direct link between EZH2 levels, chromosomal instability and metastasis. But how was EZH2 driving instability?

Chromosomal Chaos

The team discovered that EZH2 silences the tankyrase 1 gene, which normally ensures the chromosome-separating machinery works properly during cell division. This triggers a chain reaction -- the decrease in tankyrase 1 causes another protein called CPAP to build up excessively. This prompts the cell's centrosomes -- structures that pull chromosomes apart -- to multiply uncontrollably, leading to faulty divisions into three or more daughter cells.

The team showed that inhibiting EZH2 restored balance, significantly reducing metastasis in preclinical models. "For the first time, we have linked EZH2, which is an epigenetic regulator, with chromosomal instability in a mechanistic fashion," Dr. Bai said.

EZH2 inhibitors may be the first drugs that can suppress chromosomal instability directly. "This study provides a promising new approach to treating triple-negative breast cancer by targeting the root cause of metastases," said Dr. Magdalena Plasilova, associate professor of clinical surgery (pending appointment at rank), a surgical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center and an author on the study. "I see firsthand the devastating impact of metastases on patients, and this offers hope for improved outcomes and survival rates."

While Tazemetostat could be repurposed as a treatment for TNBC, other drugs might have similar or better effects. "Our discovery opens the door for clinical trials to test EZH2 inhibitors in high-risk breast cancer and potentially other cancers that are also marked by chromosomal instability, such as lung adenocarcinoma," said Dr. Mittal, who is also a member of the Englander Institute of Precision Medicine at Weill Cornell. Currently, he is planning collaborations to conduct safety tests in a clinical trial.

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