An Advance in Understanding the Mechanisms of Parkinson's

Researchers have been making good progress in recent years on understanding the mechanisms underlying Parkinson's disease. The condition progresses due to the destruction of a vital set of dopamine-generating neurons in the brain. Like many late-onset conditions, it appears that the root causes of this cell death are an exaggerated form of the harm that falls upon all of us with advancing age. Where Parkinson's has genetic influences, those influences appear to reduce the ability of these cells to maintain themselves against the accumulated damage of aging, hence leading to a faster degeneration and an earlier appearance of the condition. So it is quite possible that one of the outcomes of Parkinson's research will be the understanding necessary to boost the ability of central nervous system cells to maintain themselves in everyone, not just those who are failing more rapidly due to a poor roll of the dice in the genetic lottery.

[Researchers] have brought new clarity to the picture of what goes awry in the brain during Parkinson's disease and identified a compound that eases the disease's symptoms in mice. One of their findings was that the function of an enzyme called parkin, which malfunctions in the disease, is to tag a bevy of other proteins for destruction by the cell's recycling machinery. This means that nonfunctional parkin leads to the buildup of its target proteins, and [researchers] are exploring what roles these proteins might play in the disease.

[Researchers created] mice whose genes for a protein called AIMP2 could be switched into high gear. AIMP2 is one of the proteins normally tagged for destruction by parkin, so the genetically modified mice enabled the research team to put aside the effects of defective parkin and excesses of other proteins and look just at the consequences of too much AIMP2. The consequences were that the mice developed symptoms similar to those of Parkinson's as they aged, the group found. As in Parkinson's patients, the brain cells that make the chemical dopamine were dying.

AIMP2 was activating a self-destruct pathway called parthanatos, [named for the] poly(ADP-ribose), or "PAR," and the Greek word thanatos, which means "messenger of death." [Researchers] had previously seen parthanatos set off after events like traumatic injuries or stroke - not by chronic disease. AIMP2 triggered parthanatos by directly interacting with a protein called PARP1, which was long thought to respond only to DNA damage - not to signals from other proteins.

[The researchers] already knew of compounds drug companies had designed to block this enzyme. Such drugs are already in the process of being tested to protect healthy cells during cancer treatment. Crucially, two of these compounds can cross over the blood-brain barrier that keeps many drugs from affecting brain cells. The research team used a compound that blocks PARP1. "Not only did the compound protect dopamine-making neurons from death, it also prevented behavioral abnormalities similar to those seen in Parkinson's disease."



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