The Basque Tremor

25 October 2004 (All day)

Parkinson's. A person with PARK8 type parkinsonism (right) shows less overall activity of the neurotransmitter dopamine, compared to that in a healthy brain (left).

Researchers have found a gene that causes an inherited kind of Parkinson's disease. Because this inherited form afflicts people late in life--as does the more common, sporadic form of PD--the discovery may help uncover a cause that underlies both of them.

Parkinson's disease is not one disorder but many diseases that differ by factors such as the age at onset, the formation of protein aggregates in the brain, and the severity of muscular and cognitive decline. Geneticists follow Parkinson's-prone families to find mutated genes that cause the rare, inherited forms. They have identified about 10 of these types of Parkinson's, each caused, they believe, by mutations in certain genes.

Some of the genes have already been identified, such as parkin (ScienceNOW, 8 April 1998), which is responsible for Parkinson's type PARK2, and alpha-synuclein (ScienceNOW, 26 June 1997), which instigates type PARK1. Two years ago, researchers found a region on chromosome 12 that harbored the gene that causes PARK8. PARK8 sets in later in life, at about the same age as the common, non-inherited Parkinson's; most other heritable types strike in young- to mid-adulthood. To find the gene on chromosome 12 that causes PARK8, an international collaboration of scientists, led by Jordi Perez-Tur from the Institute for Biomedicine, Valencia, Spain, Nick Wood at the Institute of Neurology, London, UK, and Andrew Singleton at the National Institute on Aging, Bethesda, Maryland looked for mutations shared by several Basque families in Spain.

The team sequenced a handful of genes in the suspect region of chromosome 12 from 48 relatives within five PARK8-afflicted families. All 26 members who suffer from PARK8 had a mutation called R1396G; it was not present in any of the 22 healthy members. The researchers additionally found the mutation accounted for about 8% of Parkinson's disease cases in a larger, unrelated group of patients, the researchers report in 22 October Neuron Online. This mutation occurred in a gene that the researchers dubbed dardarin, after the Basque word for tremor. By examining human tissues, the team showed that messenger RNA for dardarin is made throughout the brain.

The DNA sequence of dardarin is interesting because it encodes a protein that looks like a kinase, which is an enzyme that dabs phosphate groups onto proteins to allow them to communicate with each other. That's intriguing because tau and a-synuclein--proteins often found aggregated in the brains of Parkinson's patients--are decorated with phosphate groups. Additional research will reveal whether a connection exists between these two and the new protein on the block, says neuroscientist John Trojanowski of the University of Pennsylvania in Philadelphia. "This is tremendously exciting," he says. "It will open up important new avenues of research that will hopefully become therapeutically meaningful."

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