BioWorld International Correspondent

LONDON - A new understanding of the molecular pathways that lead to Parkinson's disease might result from the discovery of a sixth gene linked to an inherited form of the condition.

The researchers who made the finding predict that it will "open novel avenues of research aimed at identifying and ultimately halting the molecular events that lead to Parkinson's disease."

Because the gene in which the mutations occur was discovered in four families from the Basque region of Spain, among others, the research team named the protein it encodes "dardarin," after the Basque word for tremor. Little is known about its function.

Jordi Perez-Tur, tenured scientist at the Institut de Biomedicina de Valencia-CSIC in Valencia, Spain, told BioWorld International: "Because the disease in the families who have this mutation is very similar to that of patients with Parkinson's disease in general, we can assume that the molecular pathways that dardarin is involved in are also involved in other cases. We now want to find out how common variations in this gene are in sporadic cases of Parkinson's disease, as well as in other familial cases."

The mutation found in the Basque families also was identified in 8 percent of 137 apparently unrelated Basque people with Parkinson's disease. That suggests that the mutation is a relatively common cause of the disease in the Basque population, the researchers said.

The work was carried out by a Spanish team led by Perez-Tur, in collaboration with a UK group led by Nick Wood, of the Institute of Neurology in London, and an American group, led by Andrew Singleton, of the National Institute on Aging in Bethesda, Md. Their work is published in the Oct. 22, 2004, issue of Neuron in a paper titled "Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease."

Perez-Tur, Wood and Singleton set out to pin down a gene linked to Parkinson's disease that previous research by a Japanese group had located on an area of chromosome 12, which they had called PARK8. However, the region contained 116 possible genes.

The European-American collaborators decided to study four Basque families and one family from the UK, in which affected individuals also had inherited the PARK8 region. Their investigations allowed them to show that affected individuals in all five families shared a much smaller region of chromosome 12, which narrowed the number of candidate genes down to about 11.

Sequencing of one of those genes, which encoded a kinase, identified a mutation inherited by the affected individuals in the families, but not by unaffected members. All four Basque families shared the same mutation, while the mutation in the UK family was different.

A search for the mutation in 1,300 chromosomes from North American controls and 160 chromosomes from Basque controls drew a blank, allowing the researchers to conclude that the mutation they had identified played a role in the cause of the disease.

Experiments showed that the gene is expressed in the adult human brain, although at a lower level than in the heart and liver. However, the authors wrote, that pattern is not unusual for genes that cause neurodegenerative diseases.

Perez-Tur and collaborators now want to search for single nucleotide polymorphisms in the PARK8 gene, to find out if there is a gene variant that increases susceptibility to Parkinson's disease.

"We also want to know what the function of the normal gene is, and how mutations alter its function to bring about Parkinson's disease," Perez-Tur said. "That's the $1 million question - how a mutation like this causes such a devastating disease."

They already have some clues. Writing in Neuron, the group said that the structure of dardarin suggests that it has a role as a cytoplasmic kinase. They added: "Because phosphorylation of proteins has been implicated in the pathogenesis of neurodegenerative disease, it is particularly tempting to hypothesize a role for dardarin in the phosphorylation of proteins central to Parkinson's disease, such as alpha-synuclein and Tau [and] dardarin may present a link between these key molecules."