A 'druggable' mechanism of tau protein pathology

A 'druggable' mechanism of tau protein pathology


In a great stride toward finding an effective treatment for early-stage neurodegenerative diseases, neurobiologists have uncovered a "druggable" mechanism of pathological tau protein aggregation.and is published in the journal Science Translational Medicine.

Tau, a protein found primarily in neurons, is typically a somewhat innocuous, very soluble protein that stabilizes microtubules in the axon -- the part of the neuron that conducts signal to other neurons.

"People think of it as the ties on railroad tracks holding the microtubule tracks together," the senior author said. However, when soluble, stable tau misfolds -- sometimes the result of a mutation of the gene that expresses it -- the resulting protein becomes insoluble and tangled, gumming up the works inside the neuron as a neurofibrillary tangle. In one of several neurodegenerative diseases caused by tau, frontotemporal dementia, the frontal and temporal lobes of the brain are impaired, resulting in problems with emotion, behavior and decision-making.

"Patients do not initially show very many, if any memory problems in this condition," the senior author said. "They tend to show more psychiatric problems, often with impulsive personalities in which they show inappropriate behaviors." Other forms in this group of conditions affect language and motor skills.

By taking skin cell samples from a few individuals who harbor tau mutations and converting them in vitro into stem cells, and then into neurons, the researchers found that three genes were consistently disregulated in those with tau mutations, one of which was of particular interest: RASD2 -- a gene expressed primarily in the brain that belongs in a family that catalyzes energy-producing molecules (GTPases) and which has been studied extensively.

"People had already talked about this gene as possibly involved in Huntington's disease, which is another neurodegenerative disease," the senior author  said. RASD2 and its more famous cousin RAS (studied heavily in cancer research) are considered "druggable," the author  explained.

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

The researchers expertise and curiosity led them to examine a GTPase called Rhes, which is encoded by the gene RASD2 and has been shown to play a role in the development of Huntington's disease. However, it wasn't Rhes's catalytic activity that piqued their interest.

"We quickly realized the obvious function of the Rhes protein -- its enzyme activity -- was not critical to what we were looking for," the senior author said.

"What we ended up focusing on was the fact that this protein and all members of its family are attached to the cell membrane in a very interesting way," the author continued. Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where, the author explained, it is attached to the inner membrane by a small carbon chain -- a farnesyl group -- through a process called farnesylation.

"There's an enzyme called farnesyl transferase that takes this protein, Rhes, and attaches it to the membrane, and we decided to focus on that reaction," the author said. "It was a bit of a jump to go in the direction."

This attachment has been the target of a couple decades and millions of dollars of cancer research under the assumption that if the Ras protein connection to the cell membrane could be interrupted, so would the signals that cause unregulated growth of tumor cells and other cancer behaviors.

"It turns out the drugs in this category, called farnesyltransferase inhibitors, have been tested in humans. They're safe," the author said. "But, they did not work in cancer."

In mice models with frontotemporal dementia, however, it seems they do. And the results are dramatic. Using the drug Lonafarnib, the researchers treated mice who at 10 weeks were erratic -- running around in circles or completely apathetic -- and by 20 weeks they were sniffing around their cage or nest building and doing other normal mouse behaviors. Scans revealed the arrest of brain tissue deterioration and inflammation. Most dramatic: The once-insoluble neurofibrillary tangles were greatly reduced, and in some areas including the hippocampus -- the memory part of the brain -- were nearly completely gone.

"The drug is very interesting," the senior author said, "It seems to have a selective effect on only the forms of tau that are predisposed to forming the neurofibrillary tangles." To prove the drug was targeting the farnsylated Rhes protein, the scientists introduced into the brains of other mouse models an inhibitory RNA gene that specifically suppresses the production of Rhes. And the results completely replicated the effects of the drug.

"This makes us begin to think that although indeed the drug is a general farnesyl transferase inhibitor, one way it's actually working is by specifically targeting the farnesylation of Rhes," the senior author said. "And, fortunately, the other farnesyl inhibitions that it's also doing are not toxic."

Now the stage is set for human trials, with a few volunteers at risk for the disease. And perhaps further down the road, the team is considering a population with frontotemporal dementia in Colombia where the senior author has conducted similar studies in Alzheimer's disease.

"We wouldn't even necessarily do an efficacy study right away," the senior author said. "We have to just first show that the drug is getting into the human brain and affecting the target."

But even that early stage may be in limbo, as the makers of Lonafarnib, currently in trials for the drug as a treatment for progeria, are reluctant to involve their product in new trials before they get their approvals. The team are pondering their options as they contemplate a potential long-awaited solution to a group of heartbreaking -- and wallet-draining -- neurodegenerative diseases.

https://www.news.ucsb.edu/2019/019394/dissolving-gordian-knot

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ffarnesyl-transferase&filter=22

Edited

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