Researchers Find Pathway Responsible for Nerve Cell Death in Parkinson’s Disease
Johns Hopkins researchers have identified a specific cell death pathway named Parthanatos — after Thanatos, the ancient Greek personification of death — that leads to the physical and intellectual degeneration associated with Parkinson’s disease.
They also found that a protein called PARP-1 is a key mediator of cell death via Parthanatos, supporting the potential therapeutic benefits of PARP inhibitors for halting Parkinson’s progression.
“Nailing down how cells die in this disease increases our hope that someday we will be able to treat and possibly cure Parkinson’s disease,” the study’s co-lead author Ted Dawson, MD, PhD, director of the Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine, said in a press release.
The study, “Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease,” was published in the journal Science.
Accumulation of a protein called alpha-synuclein into clumps known as Lewy bodies in the brain has long been linked to Parkinson’s disease progression.
This abnormal accumulation affects nerve cells, causing them to die, but how it leads to cell death was not known.
In experiments done in mice, Johns Hopkins researchers observed that the accumulation of alpha-synuclein activated a cell death pathway called Parthanatos, named after the ancient Greek mythological figure Thanatos who personified death.
They found that activation of this pathway was the main driver of nerve cell death, while other programmed cell death pathways played no role, including apoptosis — the death of cells in a controlled manner as a normal part of growth and development — and necroptosis, triggered by disease or injury.
The team subjected lab-grown mouse brain cells to clumps of alpha-synuclein and observed cell response over 14 days. Cells eventually began to die, during which they activated a protein called poly(ADP-ribose) polymerase-1 (PARP-1), a hallmark of cell death via parthanatos.
PARP-1 is one of the members of the large PARP family, a group of enzymes regulating several cellular processes such as DNA repair and genome stability, and programmed cell death.
Blocking PARP-1 with chemical inhibitors of the protein — veliparib (ABT-888), rucaparib (AG-014699), or talazoparib (BMN 673) — protected the cells from alpha-synuclein-triggered death.
To evaluate PARP-1’s role in vivo, researchers injected alpha-synuclein clumps into the brains of mice engineered to lack PARP-1. The same procedure was performed in normal (wild-type) mice.
While the wild-type controls developed many of the symptoms characteristic of Parkinson’s disease three months after injection, including muscle weakness, loss of coordination, and decreased movement, mice lacking PARP-1 were protected from these deficits. The same protection was seen in mice treated with PARP inhibitors.
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“Showing that blocking this key step in the Parthanatos pathway protected the cells against death is evidence that Parkinson’s disease kills cells through this mechanism,” said Tae-In Kam, PhD, the study’s first author and postdoctoral fellow in the Institute for Cell Engineering at Johns Hopkins.
Previous studies reported that activation of PARPs causes nerve cells to produce a sugar, called poly (ADP-ribose), or PAR, which is able to bind alpha-synuclein, increasing the likelihood for clumping.
Researchers added PAR to the clumps of alpha-synuclein before giving it to lab-grown mouse brain cells. The complex of PAR-alpha-synuclein resulted in the formation of a more neurotoxic strain of alpha-synuclein clumps — cells died 25 times faster than control cells treated with alpha-synuclein clumps alone.
They then injected either the alpha-synuclein clumps or the more toxic complex of PAR-alpha-synuclein into normal mice and observed the animals for six months.
Mice that received the PAR-alpha-synuclein complex began to show signs of degeneration at three months, twice as fast as those that received only alpha-synuclein clumps, whose symptoms began only six months after injection.
“The PAR/alpha synuclein combination is not only faster at killing neurons, it’s a more potent toxin,” Kam said.
To study whether PAR also plays a role in human Parkinson’s disease, the researchers measured the levels of the sugar PAR in the cerebrospinal fluid of 21 Parkinson’s disease patients at various stages of the disease and in 33 healthy subjects.
The levels of PAR in Parkinson’s patients were almost twice that found in the cerebrospinal fluid of healthy subjects.
“Additionally, one out of four of our samples showed a correlation between PAR concentration and the disease’s progression,” Kam said.
While more research in humans is needed to further validate these results, this study suggests that therapies inhibiting PARP-1 activation may help delay or even halt Parkinson’s disease in humans.
“If PARP inhibitors work in human Parkinson’s disease patients as they have in mice, they could be protective of cells already affected by Parkinson’s disease, but also slow the transmission of these harmful proteins to new cells,” said Valina Dawson, PhD, professor of neurology at Johns Hopkins and co-lead author.