Murder on the Parkinson's Express: A protein villain might kill brain cells by taking a neuron guardian hostage (Neurodegeneration)
Authors: Chen Ingfei 
Published: August 2003

The cause of Parkinson's disease is one whodunit that would tax Hercule Poirot's little gray cells. The murder victims are brain cells that make the neurotransmitter dopamine. Several clues have set scientific sleuths hard on the trail of a protein dubbed α-synuclein. A new report now pulls together evidence into a cohesive theory on how the protein might knock off brain cells and suggests that it delivers its deadly blow in part by holding captive a molecule that protects neurons.

Scientists put α-synuclein high on their suspect list because the insoluble form of the protein piles up inside dopamine-producing neurons in the part of the brain--the substantia nigra--ravaged in Parkinson's (see
"A Clique's Undoing"
and
Andersen Review
). Furthermore, mutations in the α-synuclein gene cause rare familial forms of the illness, and when dopamine-producing neurons are engineered to churn out α-synuclein in culture, they commit suicide in a process known as apoptosis.

Previous work has implicated dopamine as a potential lethal conspirator; adding the chemical to α-synuclein-spewing brain cells causes apoptosis. But Xu and colleagues wondered whether a neuron's own natural supply of dopamine is toxic. To find out, they prevented neurons in culture packed with α-synuclein from producing the neurotransmitter. That intervention saved the cells. The results are the first to demonstrate that even the small amount of dopamine made by human brain cells can foster their demise, says neurobiologist Bruce Yankner of Harvard Medical School in Boston, who led the group.

The next step was to identify a murder weapon. Other studies had shown that α-synuclein colludes with dopamine to generate destructive free radicals (see
"The Two Faces of Oxygen"
). Xu and colleagues wanted to test whether this oxidative surge spurs apoptosis, so they exposed their neurons to antioxidants, which squelch the radicals. Cell suicide rates dropped by as much as half. "The results really nail down the cause and effect," Yankner says.

To determine whether α-synuclein overload is a problem in Parkinson's, the team studied the substantia nigra of deceased patients. In their cell culture experiments, the investigators identified what they believe is the neurotoxic perpetrator. Although they expected a gummy cluster, they instead pinpointed a soluble protein conglomeration containing α-synuclein. Supporting their suspicions, amounts of this mélange were about 70% higher in Parkinson's patients than in people who had died from other causes, they discovered.

The team then found a protein called 14-3-3 inside the assembly. Previous work had established that this molecule binds to and inhibits proteins that promote cell death, and that α-synuclein also binds to 14-3-3. The new results suggest that α-synuclein detains the guardian from its apoptosis-fighting duties. "The cells are less protected from the detrimental effects," Yankner speculates.

Murderous α-synuclein might actually be a good citizen turned bad. It apparently saves neurons in dopamine-free zones of the brain. Overproduction of α-synuclein decreased cell death in neurons from the cortex, the team found.

The report knits together several strands of evidence, says neuroscientist Eliezer Masliah of the University of California, San Diego: "It links concepts and represents a logical and coherent story."

--Ingfei Chen

J. Xu, S.-Y. Kao, F. J. S. Lee, W. Song, L.-W. Jin, B. A. Yankner, Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson disease.
Nat. Med.
8
, 600-606 (2002).
[Abstract]
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