A New Approach to Targeting Tau Aggregation in Neurodegenerative Disease

Researchers here report on discovering that an existing farnesyltransferase inhibitor drug reverses the accumulation of altered tau protein aggregates in a mouse model. The death and dysfunction of nerve cells in the neurodegenerative conditions known as tauopathies is driven by the formation of neurofibrillary tangles, made of tau protein. That in turn has deeper causes, such as the chronic inflammation produced by senescent cells and disruption of immune cell activity in the central nervous system, one of which is no doubt being adjusted in some way by the action of the drug in this case. As in all such quite indirect mechanisms, there is the question as to whether results in mice will translate to humans in any useful way. In the case of an existing drug, there is at least a shorter path to an answer.

Tau, a protein found primarily in neurons, is typically a somewhat innocuous, very soluble protein that stabilizes microtubules in the axon. However, when soluble, stable tau misfolds 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.

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, 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. A GTPase called Rhes is encoded by the gene RASD2. Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where it is attached to the inner membrane by a small carbon chain - a farnesyl group - through a process called farnesylation.

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. The drugs in this category, called farnesyltransferase inhibitors, have been tested in humans. 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. 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.

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

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