UCSB Neuroscientists Reveals Path for the Treatment of Potential Dementia

By Sonia Fernandez, UC Santa Barbara

In an effort to obtain effective treatment for early-stage neurodgenerative diseases, a pathological protein “concentration” mechanism has been found by Kenneth Santa Barbara's neurobiologist Kenneth S. Kosik. For millions of people at risk of frontotemporal dementia and many other similar conditions including Alzheimer's, this could change towards a significant management of signs or a total prevention of some of the diseases. we are most disastrous.

“We are very excited about this,” said Kosik, Professor of Neurology UCSB Harriman and co-director of the campus Neurology Research Institute. While much work needs to be done, the evidence promising for this controllable mechanism is increasing and the stage is set for future investigations. Following a recent stop on clinical trials for Aducanumab, a drug that once looked at promising Alzheimer's treatment, this development is a sign of hope.

The team's paper, “A Fatesyl Transferase Inhibitor to Targets in Zones, reduces Tau Pathology in Mice with Tauopathy,” in Science Transal Medicine.

Tau is usually a very soluble, highly soluble protein, which is mainly found in neurons, which stabilizes microtubules in the axis – the part of the neurone that makes a sign for other neurons.

“People think of it as the connections on railway tracks that have the microtubule tracks together,” said Kosik. However, when soluble, stable tau-imbalanced solutions – sometimes as a result of mutation of the gene that indicate it – the resulting protein becomes insoluble and stringing, making the works inside the neurone as a result. neurotic bathing. t In one of the various neurodgenerative diseases caused by string dementia, the initial and time weaknesses of the brain are impaired, creating problems with emotion, behavior and decision-making.

“Patients do not first display many memory problems in this condition,” said Kosik. “They usually show more psychiatric problems, often with impulsive personalities in which they exhibit inappropriate behavior.” Other forms in this group influence language and motor skills.

Taking samples of skin cells from some people who treat mutations and incorporate them in vitro into stem cells, and then into neurons, the researchers found that three surrenders were continuously deregulated with those with mutations, who were interested. one of them: RASD2 – a gene that is mainly reflected in the brain associated with a family that catalyzes energy-producing molecules (GTPases) and has been extensively studied.

“People have already said that this gene was associated with Huntington's gene, which is another neurodegenerative disease,” said Kosik. RASD2 and its cousin RAS (who has been extensively studied in cancer research) are considered as "druggable," explained Kosik.

“There are potential drugs or drugs or small molecules that are out there that could affect the levels of this gene,” he said.

From cancer drugs that have failed to treat dementia may be possible

If you are neuroscientist who is interested in mutations and remedies in the conditions they create, you know that you are in your long game. The nature of these diseases – genetic and neurological – means that advanced studies must be highly regulated and often very difficult and expensive to come by and any drug developed must be both effective and non-toxic. This was the case for Kosik and the author of the paper, a postdoctoral researcher, Israel Hernandez, who was studying the protein tones and genes for coding proteins that could contribute to or combat a month. ship.

The combination of Kosik, Hernandez and their peers' expertise and curiosity led them to examine GTPase called Rhes, which is encoded by the RASD2 gene and demonstrated a role in the development of Huntington's disease. However, it was not a catalyst activity of Rhes which promoted its interest.

“We quickly realized that the clear function of protein Rhes – its enzyme activity – was not vital to what we were looking for,” said Kosik.

“Our focus on the end was that this protein and all its family members are connected to the cell membrane in a very interesting way,” he continued. Like his cousins ​​in the Ras field, Rhes is a signaling protein that makes his work on the surface of the cell, as Kosik explained, that he is connected to the inner film with a small carbon chain – a opinion group – through a process called view .

“There is an enzyme called a vinyl transferase that takes this protein, Rhes, which draws it on the film, and we decided to focus on that reaction,” said Kosik. “It was a little jump to go in the direction.”

This attachment was the target of decades and millions of cancer research dollars under the assumption that the introduction of the protein Race connection to the cell film could cause the signs that cause uncontrolled growth of tumor cells and other cancer behaviors.

“The drugs in this category, called barnesyltransferase protectors, have been tested in humans. They are safe, ”said Kosik. “But they didn't work with cancer.”

In mice with initial dementia models, however, they seem to do. And the results are dramatic. Using the Lonafarnib drug, the researchers spent mildly mice for 10 weeks – running around in circles or totally sympathetic – and by 20 weeks they were sniffing around building a cheese or nest and making a mock-up of a mouse. other. Scans indicated that a deterioration in brain tissue and inflammation was arrested. The most dramatic: The insoluble neurofibrillary tangles, and in some areas, including the hippocampus – were greatly reduced – the memory part of the brain – was almost completely gone.

“The drug is very interesting,” says Kosik, “It seems to have an optional effect on the types of tes that are presumed to create neurofibrillary nerves.” To prove that the drug was focusing on protein Fairness, the scientists enter the brains of other mouse models RNA gene is a preventive gene that specifically violates Rhes production. And the results were fully replicated the effects of the drug.

“As a result, we consider that the drug is a general inhibitor of the morphology transferase, but it is working specifically by focusing specifically on Rhes declaration,” said Kosik. “And, fortunately, the other births are banned that it is also not toxic.”

On the spot

The publication of this paper is a milestone in the efforts of the researchers for years to acquire land on the hill-top and tauopathic neurodegeneration. As there was not enough grueling research, as they had to search the world to get the signature from a team member who was heading towards the hill – at Mt. Everest. Hernandez celebrated the birth of her first child on the day the paper was adopted.

But the race is not yet. Now the stage is set for human trials, a few volunteers at risk of the disease. And perhaps further down the road, the team is thinking about a population with initial dementia in Colombia where Kosik has conducted similar studies in Alzheimer's disease.

“We don't even have to do an efficiency study,” said Kosik. “We must first show that the drug is entering the human brain and interfering with the goal.”

But this early step could be in the heart, as Lonafarnib makers, who are currently in trials for the drug as a treatment for progeria, are reluctant to bring their product into new trials before they get their approvals. . Kosik and his team are considering their options as they consider long-term prospects for a group of aggressive diseases – and wallet-neurodegenerative drainage.

“It's a big challenge,” said Kosik. “I'm working on that.”

Gabriel Luna, Jennifer N. Rauch, Michael Giroux, Daniel Boctor, Youssef E. Sibih, Alexander A. Kang, Cassidy Hinman, Vesna Cerovac, Elmer Guzman, Honjun Zhou and Steven K. Fisher from UC Santa Barbara; as well as Surya A. Reis and Stephen J. Haggarty from Harvard Medical School. Nadia J. Storm, Antonio Diaz and Ana M. Cuervo at the Albert Einstein Medical College, researched, as well as Celeste M. Karch of the University of Washington; Cezary Zekanowski from the Polish Academy of Sciences; and Alison Goate from Icahn Medical School at Mount Sinai.

news.ucsb.edu

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