Brain pigment and Parkinson's disease.

Brain pigment and Parkinson's disease

Scientists recently observed that a chemical compound found in synthetic heroin and other illegally manufactured opiates causes brain damage and clinical symptoms that closely match Parkinson's disease (SN: 10/5/85, p. 212). Some researchers believe Parkinson's may be caused by a combination of exposure to the same chemical, known as MPTP, or related compounds in food and other environmental sources and normal brain-cell loss due to aging. But the reason why MPTP destroys only a small, crucial brain area has remained unclear.

In the Feb. 28 SCIENCE, investigators at Johns Hopkins University in Baltimore offer a possible explanation for MPTP's selectivity. After MPTP is converted to the highly toxic substance MPP.sup.+ in the brain, it is pumped into cells that produce the neurotransmitter dopamine and sticks to those that contain the natural pigment neuromelanin, say Robert J. D'Amato, Zoe P. Lipman and Solomon H. Snyder. Most brain areas with the pigment have nerve terminals that channel MPP.sup.+ out of dopamine cells, they explain, but the substantia nigra -- the portion of the brain implicated in Parkinson's disease -- contains plenty of neuromelanin and few of the protective nerve terminals.

D'Amato and his colleagues came up with this model after first observing that MPP.sup.+ binds to melanin synthesized from dopamine at much higher concentrations than it binds to melanin synthesized from another neurotransmitter, norepinephrine. They then observed that MPP.sup.+ strongly binds to dopamine-rich neuromelanin isolated from a monkey's substantia nigra.

Low does of MPTP cause extensive cell loss in the substantia nigra of both humans and monkeys, note the researchers. In mice, however, there is no marked loss of neurons, even at higher MPTP doses. There is little or no neuromelanin in the substantia nigra of rodents, they point out, while humans and monkeys have large amounts of the pigment in the substantia nigra.

Although the pigmented locus ceruleus region of the brain also contains neuromelanin, it is largely immune to the cell-destroying effects of low doses of MPTP. The investigators propose that once MPTP is converted to MPP.sup.+ and enters the locus ceruleus, it is accumulated by a dense network of catecholamine (dopamine, norepinephrine and epinephrine) nerve terminals that prevent the substance from entering cell bodies.

"In theory, the key events is that MPP.sup.+ is pumped into dopamine [neurons] by the dopamine uptake system," says Snyder. "But in general, this is not enough. It looks like neuromelanin greatly assists in the killing of brain cells."

The proposed neuromelanin connection, however, has not been endorsed by all MPTP researchers. "The observation [of the Hopkins scientists] is fascinating, but I'm slightly skeptical," says J. William Langston of Stanford University. "I'd label this under the category of an interesting hypothesis that hasn't been thoroughly tested."

Langston and his colleagues recently observed that MPTP does cause cell destruction in the substantia nigra of older mice, a finding that is consistent with the age-related progression of Parkinson's disease. As a result, he says, "I don't believe neuromelanin is part of the key [to MPTP's effects]." Snyder doubts that older mice are as sensitive to MPTP as humans and monkeys are, but at this point, holds Langston, a satisfactory theory for the findings from various laboratories is not possible.