The path of cell death more clearly identified for Parkinson's disease-ScienceDaily

Results of the study, published on November 2 in Science, suggest promising new targets for drugs that may interrupt the progression of Parkinson's disease.

The researchers said the study focused on Parthanatos, a specialized "programmed" pathway to cell death, named Thanatos, the ancient Greek personification of death, as a key factor in the breakdown of nerve cells that is a marker of Parkinson's disease. It differs from other known forms of programmed cell death such as apoptosis (normal part of growth and development) and necroptosis (usually cell death due to disease or injury). The first step in the fight against Parkinson's disease is the accumulation of misfolded proteins in brain neurons. These proteins, known as alpha synuclein, have long been linked to the progression of Parkinson's disease, but their specific effect on brain cells has not been clear.

"By learning how cells die in this disease, we hope to someday be able to treat and eventually cure Parkinson's disease," said Ted Dawson, MD, Ph.D., director of the Institute of Cell Engineering and Professor of Neurology at the School of Medicine at Johns Hopkins University.

To learn more about the "way" of cell death, Parkinson's cells travel, the research team treated brain cells from laboratory-developed mice with preformed tufts of alpha-synuclein and observed their response for 14 days. When brain cells began to die, the researchers found that they had "activated" a protein called PARP1, a gateway to cell death via the Parthanatos.

They then tested whether blocking PARP1 could save cells from certain death. In an additional experiment, the researchers again added lumps of alpha synuclein to healthy mouse brain cells, and then treated them with one of three PARP1 blocking drugs: Véliparib (ABT -888), rucaparib (AG-014699) or talazoparib (BMN 673). ), all currently used by oncologists to treat breast and ovarian cancers. The researchers found that cells treated with these drugs were protected from death at 14 days.

To test this principle in live mammals, the research team injected masses of alpha synuclein into the brain of normal mice and genetically modified mice so as not to own the PARP gene. The researchers found that normal mice were starting to show muscle weakness, loss of coordination, and decreased movement, as shown by mouse adhesion strength tests and their ability to descend a vertical pole three months later. the treatment. However, mice lacking PARP and normal mice treated with PARP inhibitors showed no decline.

"Showing that blocking this key step of the Parthanato pathway protecting cells from death proves that Parkinson's disease kills cells by this mechanism," said Tae-In Kam, Ph.D., lead author of the program. study and postdoctoral fellow of the Institute. for cell engineering from the Johns Hopkins University School of Medicine.

Previous studies have shown that PARP causes neurons to create a sugar called PAR, which binds to alpha-synuclein and increases the rate at which alpha-synuclein proteins agglutinate. Kam wondered if the increase in PARP1 seen in Parkinson's cells could have a similar effect.

To test this hypothesis, the researchers added PAR and preformed alpha-synuclein lumps to mouse brain cells developed in the laboratory. They discovered that the combination of PAR and alpha synuclein formed a different, more neurotoxic, strain of alpha synuclein mass. Cells treated with this combination died 25 times faster than their counterparts receiving alpha-synuclein alone.

To validate this observation, the research team repeated the experiment in normal mice. The researchers administered the preformed alpha-synuclein lumps or the more toxic combination of PAR / alpha synuclein in the mouse brain and observed them again for six months. Mice that received only alpha synuclein lumps began to show signs of degeneration six months after treatment. However, the mice that received the combination treatment showed twice as fast degeneration, showing significant degeneration at only three months.

"The PAR / alpha synuclein combination is not only faster to kill neurons, it's a more potent toxin," Kam says.

To determine if this mechanism might play a role in human Parkinson's disease, researchers collected cerebrospinal fluid from 21 patients with Parkinson's disease at various stages of the disease, as well as fluid samples taken from 33 healthy people. The team then measured the amount of PAR in each sample. They discovered that there was about twice as much PAR in samples from people with Parkinson's disease.

"In addition, one in four samples showed a correlation between PAR concentration and disease progression," says Kam.

The researchers pointed out that much more research still needed to be done before their discoveries could be applied to humans. However, if other experiments supported their results, they hoped to work on clinical trials with drug manufacturers currently producing drugs targeting PARP to test their capacity. these drugs to slow down or even stop Parkinson's disease in humans.

"If PARP inhibitors work in human patients with Parkinson's disease as in mice, they could protect cells already affected by Parkinson's disease, but also slow down the transmission of these harmful proteins to new cells." says Valina Dawson, Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine.

Parkinson's disease is a progressive disorder of the nervous system that affects an estimated one million people in the United States, according to the Parkinson Foundation. Early symptoms include tremors, sleep disturbances, constipation, and movement or walking difficulties, which eventually lead to more severe symptoms such as loss of motor skills and speech and dementia. Most people begin to develop symptoms beginning at age 60, but cases have been reported in patients as young as 2 years old.

This work was funded by grants from the National Institute of Neurological Disorders and Stroke (P50NS38377, R37NS067525, NS082205, U01NS082133 and U01NS097049, U01NS100610), the JPB Foundation and the Jane and Lee Seidman Fund.