April 04, 2019

Mouse model develops Parkinson's just like humans, opening the door to more accurate drug screening

April 04, 2019

LA JOLLA, CA To study a disease, scientists need to be able to track its progression in a living organism, such as a mouse. But scientists studying Parkinson's disease have found it challenging to design a genetic animal model that mimics specific aspects such as progressive neuronal cell death, motor symptoms and behavioral changes seen in the inherited form of Parkinson's disease.

Now, scientists at Scripps Research have found a way to tweak the mouse genome to make a mouse model that better mimics Parkinson's disease in humans. The new research, published in the Nature journal Communications Biology, will make it possible to screen drug candidates more reliably and investigate the root cause of the disease.

This is the first mouse model that really reflects one form of inherited Parkinson's disease, says Steven Reed, PhD, a professor at the Department of Molecular Medicine. This is a better model for testing if a drug really has an impact.

It has been known for some time that people who inherit mutations in the gene that encodes a protein called parkin develop the disease at an early age. However, scientists have found that when the gene for parkin is mutated in mice, the mice do not get the disease. This was a frustrating problem because it limited the tools available to study the disease.

The researchers in the new study aimed to find a more useful mouse model. They built on their previous work, which showed parkin works together with two other proteins, Fbw7 and Mcl-1, in a pathway that protects neurons from apoptosis, the kind of cell death that causes Parkinson's symptoms. The work predicted that when parkin is mutated, neurons should have less Mcl-1, leading to their death.

To their surprise, experiments spearheaded by Scripps Research staff scientist and study first author Susanna Ekholm-Reed, PhD, revealed that when parkin is mutated in mice, neurons are actually rewired to produce more Mcl-1. The increased Mcl-1 has a neuroprotective effect and compensates for the lack of parkin, preventing Parkinson's-like symptoms from developing something that apparently doesn't happen in humans.

Next, the researchers studied what happened if they removed one copy of the gene that encodes Mcl-1 in the mice. The results were striking.

Like human patients, the mice developed Parkinson's gradually. The disease takes 20 to 30 years to develop in humans, and it took about a year to develop in the mice. That is about equivalent in terms of the mouse time scale, says Reed. Our study provides proof-of-concept that this pathway really exists in live organisms.

This was an exciting finding, and it shows the potential advantage of using this model over other Parkinson's models.

While scientists today can mimic the symptoms of the disease by using toxins that rapidly kill mouse brain cells, these models do not show the same slow disease progression seen in human patients and drug developers can't study how their therapies could affect disease progression. The new mouse model would more closely simulate the true nature of Parkinson's.

The new mouse model also shows similar motor control symptoms as humans with Parkinson's. This was clear in an experiment where the mice had their paws painted to track where they placed their feet as they walked.

One of the clear symptoms of human Parkinson's disease is a gait problem, where patients walk in a very characteristic staggering kind of way, says Reed. So it's interesting that the mouse model of the disease also reflects that.

Now that the scientists have solved one big problem in Parkinson's research, they are planning to move on to a lingering question in the field: why do only certain neurons die in Parkinson's patients?

The brain cells that die are the dopamine-producing neurons in a region that controls motor function, called the substantia nigra. Scientists know the die-off can be caused by parkin mutations, but parkin is expressed in all cells throughout the body. So why is this region so vulnerable?

The new mouse model also has cell die-off in this brain region, giving researchers a chance to test their theories and even screen drug molecules that may prevent the disease from taking hold.

We are working on using the information on the pathway we found to develop small molecules that target Fbw7 and could be effective in slowing the progression of Parkinson's disease, Reed says.

Additional authors of the study, Reducing Mcl-1 gene dosage induces dopaminergic neuronal loss and motor impairments in Park2 knockout mice, were Robert Baker, David Stouffer, Martha Henze, Jeanne F. Loring and Elizabeth A. Thomas of Scripps Research; and Alexandre R. Campos and Dieter A. Wolf of Sanford Burnham Prebys Medical Discovery Institute.

This study was supported by the National Institutes of Health (grants NS059904 and GM105802) and the California Institute for Regenerative Medicine (CIRM, grant DISC2-09073).

Molecular Medicine Reed, Steven

LINK:	https://www.scripps.edu/news-and-events/press-room/2019/20190404-reed-...
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