Breakthrough in Parkinson’s Treatment Could Come from a Single Protein


One single protein could be the key to developing groundbreaking treatments for various neurodegenerative diseases including Alzheimer’s, Huntington’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS). What these diseases all have in common are that they’re triggered by proteins misfolding and accumulating in neurons within the brain. This causes devastating damage to the cells, eventually killing them off. However, in a new study carried out by Steven Finkbeiner MD, Ph.D., and the team at the Gladstone Institutes they discovered a protein called Nrf2 was able to prevent cell death by restoring the disease-causing proteins back up to a healthy range.

The Nrf2 protein was tested in two different Parkinson’s disease models which consisted of cells with mutated versions of the protein LRRK2 and a–synuclein. With the Nrf2 activated, the cell was able to remove excess LRRK2 and a-synuclein from it. Gaia Skibinski, Ph.D., and a staff research scientist at Gladstone say. “Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now. Overexpressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”

During the study, the researchers used both rat and human neurons created from induced pluripotent stem cells and programmed then to express Nrf2 plus either a-synuclein or LRRK2. The researchers then marked and tracked the individual neurons over a period to analyze their protein levels and to keep an eye on their overall health too. During the study, the researchers discovered that the way in which Nrf2 worked to remove either LRRK2 or a-synuclein from the cells differed depending on which it was. For removing LRRK2, NRrf2 forced the protein to form into clumps that stayed within the cells without causing it any harm. With regards to the a-synuclein, Nrf2 reduced the levels of the protein within the cell by accelerating the breakdown and clearance of it.

Finkbeiner is senior author on the paper, and he says, “I am very enthusiastic about this strategy for treating neurodegenerative diseases. We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve every found. Based on the magnitude and the breadth of the effect, we want to understand Nrf2 and its role in protein regulation better.” The team is now hoping to discover other key players in the protein regulation process that can interact with Nrf2 to produce more positive results.

CHANGES IN EYE CAN PREDICT CHANGES IN BRAIN


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Gladstone scientists show that retinal thinning can be used as an early marker for frontotemporal dementia, prior to the onset of cognitive symptoms.

Researchers at the Gladstone Institutes and University of California, San Francisco have shown that a loss of cells in the retina is one of the earliest signs of frontotemporal dementia (FTD) in people with a genetic risk for the disorder—even before any changes appear in their behavior.

Published today in the Journal of Experimental Medicine, the researchers, led by Gladstone investigator Li Gan, PhD and UCSF associate professor of neurology Ari Green, MD, studied a group of individuals who had a certain genetic mutation that is known to result in FTD. They discovered that before any cognitive signs of dementia were present, these individuals showed a significant thinning of the retina compared with people who did not have the gene mutation.

“This finding suggests that the retina acts as a type of ‘window to the brain,’” said Dr. Gan. “Retinal degeneration was detectable in mutation carriers prior to the onset of cognitive symptoms, establishing retinal thinning as one of the earliest observable signs of familial FTD. This means that retinal thinning could be an easily measured outcome for clinical trials.”

Although it is located in the eye, the retina is made up of neurons with direct connections to the brain. This means that studying the retina is one of the easiest and most accessible ways to examine and track changes in neurons.

Lead author Michael Ward, MD, PhD, a postdoctoral fellow at the Gladstone Institutes and assistant professor of neurology at UCSF, explained, “The retina may be used as a model to study the development of FTD in neurons. If we follow these patients over time, we may be able to correlate a decline in retinal thickness with disease progression. In addition, we may be able to track the effectiveness of a treatment through a simple eye examination.”

The researchers also discovered new mechanisms by which cell death occurs in FTD. As with most complex neurological disorders, there are several changes in the brain that contribute to the development of FTD. In the inherited form researched in the current study, this includes a deficiency of the protein progranulin, which is tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm.

Scientists come closer to ‘mending broken hearts’ by using gene therapy to … – The Independent


Scientists have come a step closer to being able to repair the damage done by heart attacks, using a “cocktail of genes” to transform scar tissue into working heart muscles.

Novel techniques to “mend broken hearts” using gene therapy and stem cells represent a major new frontier in the treatment of heart disease.

In the latest breakthrough, achieved by researchers at the Gladstone Institute of Cardiovascular Disease in California, researchers were able to re-programme scar-forming cells into heart muscle cells, some of which were capable of transmitting the kind of electrical signals that make the heart beat, according to the latest issue of the Stem Cell Reports journal.

The same team demonstrated their technique last year in live mice, transforming scar-forming cells, called fibroblasts, into beating heart muscle cells, but this is the first time that human fibroblasts have been re-programmed in this way.

So far, the work with human fibroblasts has only been done in the lab, but it paves the way for new treatments for heart attack victims. Researchers said that the “cocktail of genes” used to regenerate cells could one day be replaced with “small drug-like molecules” that would offer safer and easier delivery.

“We’ve now laid a solid foundation for developing a way to reverse the damage [done by a heart attack] —something previously thought impossible — and changing the way that doctors may treat heart attacks in the future,” said Dr Deepak Srivastava, director of cardiovascular disease at the Gladstone Institutes. “…Our findings here serve as a proof of concept that human fibroblasts can be re-programmed successfully into beating heart cells.”

In 2012, Dr Srivastava and his team reported in the journal Nature that, by injecting three genes into the hearts of live mice that had been damaged by heart attack, fibroblasts could be turned into working heart cells.

The scientists attempted the same technique using human fibroblasts from foetal heart cells, embryonic stem cells and neonatal skin cells, injected with genes in petri dishes in the lab. An increased number of genes was required to transform the human cells, and the efficiency of the transformed cells was low, but the team were encouraged by the results.

“While almost all the cells in our study exhibited at least a partial transformation, about 20 per cent of them were capable of transmitting electrical signals – a key feature of beating hearts,” said Gladstone staff scientist Ji-dong Fu, the study’s lead author.

The number of people who survive heart attacks has increased considerably in recent decades. The British Heart Foundation (BHF) said earlier this year that 70 per cent of women and 68 per cent of men were now surviving. However, success in keeping people alive after a heart attack has led to a rise in the number of people suffering from the long-term after-effects, which include debilitating heart failure.

Heart failure occurs when the heart cannot function efficiently and can be caused by the damage done to the heart muscle during heart attack. More than 750,000 people in the UK suffer from heart failure.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: “This research represents a small but significant step forward.  Last year these scientists had a real breakthrough when they turned fibroblasts – the cells that form scarred heart tissue – in the hearts of mice into beating heart cells, by injecting them with a ‘cocktail’ of different genes.

“Now, using a different combination of genes, they have managed to turn human fibroblasts into beating heart cells in a culture dish. This process is still a long way from the clinic, but advances like this bring us closer to the likelihood that we could one day use these techniques to mend human hearts.”

Source: Independent.uk

Arc protein ‘could be key to memory loss’, says study.


Scientists have discovered more about the role of an important brain protein which is instrumental in translating learning into long-term memories.

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Writing in Nature Neuroscience, they said further research into the Arc protein’s role could help in finding new ways to fight neurological diseases.

The same protein may also be a factor in autism, the study said.

Recent research found Arc lacking in the brains of Alzheimer’s patients.

Dr Steve Finkbeiner, professor of neurology and physiology at the University of California, who led the research at Gladstone Institutes, said lab work showed that the role of the Arc protein was crucial.

“Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day,” he said.

Further experiments revealed that Arc acted as a “master regulator” of the neurons during the process of long-term memory formation.

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Scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory centre, in Alzheimer’s disease patients.”

Dr Finkbeiner

The study explained that during memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories.

The authors found that it was Arc that directed this process, from inside the nucleus.

Dr Finkbeiner said people who lack the protein could have memory problems.

“Scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory centre, in Alzheimer’s disease patients.

“It’s possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer’s.”

The study says that dysfunctions in Arc production and transport could also be a vital player in autism.

The genetic disorder Fragile X syndrome, for example, which is a common cause of both mental disabilities and autism, directly affects the production of Arc in neurons.

The Californian research team said they hoped further research into the Arc protein’s role in human health and disease would provide even deeper insights into these disorders and lay the groundwork for new therapeutic strategies to fight them.

Source: BBC