The international research team reported finding the gene in a mutant form in five families from Spain and the United Kingdom. They have named the protein "dardarin" after the Basque word for tremor.
The researchers, led by Jordi Pérez-Tur, Nick Wood, and Andrew Singleton, were seeking to pinpoint the gene that caused a form of PD called PARK8, which was first reported in 2002. Their search was spurred by the knowledge that earlier discoveries of other genetic mutations underlying rare forms of PD had yielded insight into PD and aided design and testing of drug treatments.
Until their studies, it was only known that PARK8 was caused by a mutation in a gene somewhere along a chromosomal region, or locus, that contained about 116 genes.
The researchers had identified four families from the Basque region of Spain and one from the United Kingdom that showed evidence of having PARK8 PD. Their systematic analyses of the PARK8 locus led them to track down mutations that all had in the gene encoding dardarin.
Evidence implicating dardarin includes the fact that it is expressed throughout the brain and that the characteristic mutations in dardarin are not present in more than 1400 corresponding chromosomes from people without PD.
One of the characteristic mutations was also identified in 8% of 137 apparently unrelated Basque people with PD. According to the researchers, that figure suggests that this mutation that underlies PARK8 PD is a relatively common cause of the disease in the Basque population.
Also, within the families they studied, people with PD were found to carry the mutation in dardarin, while those who were unaffected did not.
Although the function of dardarin is not known, they said, it has the characteristics of a molecular switch called a kinase. Such enzymatic switches activate other protein enzymes by attaching a phosphate to them -- called phosphorylation.
"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 PD..." wrote the researchers.
Coro Paisán-Ruíz, Shushant Jain, E. Whitney Evans, William P. Gilks, Javier Simón, Marcel van der Brug, Adolfo López de Munain, Silvia Aparicio, Angel Martínez Gil, Naheed Khan, Janel Johnson, Javier Ruiz Martinez, David Nicholl, Itxaso Marti Carrera, Amets Saénz Pena, Rohan de Silva, Andrew Lees, José Félix Martí-Massó, Jordi Pérez-Tur, Nick W. Wood, and Andrew B. Singleton: "Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease"
The other members of the research team include Coro Paisán-Ru?z, Javier Simón, Sivia Aparicio, and Jordi Pérez-Tur from the Institut de Biomedicina de València-CSIC; Nick W Wood and Shushant Jain from the Institute of Neurology in London; Shushant Jain, William P Gilks, Naheed Khan, Rohan de Silva, and Andrew Lees from the Reta Lila Weston Institute of Neurological Studies; E Whitney Evans, Marcel van der Brug, Janel Johnson, and Andrew B Singleton from the National Institute on Aging; Adolfo López de Munain, Itxaso Marti Carrera, Amets Saenz Pena, and José Félix Martí-Massó from the Hospital Donostia; Angel Martínez Gil from the Hospital Ntra. Sra. de la Antigua; Javier Ruiz Martinez from the Hospital de Mendaro; and David Nicholl from the Queen Elizabeth Hospital.
Thanks to the Reta Lila Weston Trust for Medical Research for funding S.J., A.L., and R.d.S. Thanks for the Parkinson's Disease Society for funding N.W.W. and D.N.
Publishing in Neuron online on October 22, 2004. DOI: 10.1016/S0896627304006890
Journal
Neuron