29 October 2004. Biochemists, cell and molecular biologists, start your engines! You now have another Parkinson protein challenge. The gene that causes PARK8 Parkinson disease has been cloned by a team of researchers from Spain, England, and the United States. As described in a 22 October article in the early, online Neuron, the protein product "dardarin" may be a kinase, which should whet the appetites of the protein phosphorylation crowd.
Based on factors such as age-of-onset and clinical presentation, researchers have divided familial parkinsonism into distinct, numbered disorders—about 10 to date. These categories have been productively married with modern genetics to identify mutations in four different proteins that lead to inherited forms of PD: PARK1/α-synuclein, PARK2/parkin, PARK6/PINK (see ARF related news story), and PARK7/DJ-1 (see ARF related news story).
PARK8, identified only in 2002 (Funayama et al., 2002) is an especially attractive prize. Unlike many of the other familial parkinsonian conditions, which begin early in life, PARK 8 resembles sporadic Parkinson disease: It strikes late in life, and its clinical phenotype is relatively uniform and similar to the sporadic disease. Although the clinical phenotype of PARK8 is relatively uniform, its pathology may vary widely.
The research team that identified the gene responsible for PARK8 comprised Andy Singleton and his colleagues at National Institute on Aging in Bethesda, Maryland, Jordi Pérez-Tur and colleagues at the València Institute of Biomedicine and other institutions in Spain, and Nick Wood and colleagues at the Institute of Neurology in London and other institutions in England. These researchers had previously identified four families from Spain's Basque region and one from England with PARK8. In the current study, they were able to reduce the area of chromosome 12 originally identified by Funayama and colleagues (12p11.2-q13.1) to a short 2.6 Mb region containing only 11 genes. Among these, they discovered two separate missense mutations—one segregating with affected members in the Basque families and another within the English family—in a gene encoding a 2482 a.a. protein the authors chose to name "dardarin," from the Basque word dardara, meaning tremor.
Neither the Basque family variant, R1396G, nor the English, Y1654C, was found in chromosomes of non-PD control populations in North America (1300 subjects) or Spain (160 Basque subjects). Interestingly, however, the R1396G mutation was found in eight percent of 137 Basque PD patients (30 familial, 107 sporadic) unrelated to the four kindreds studied here. Because PARK8 has a late onset, and some potential patients may die before the disease manifests itself, this raises the possibility that more sporadic cases, at least in the Basque population, are in fact R1396G PARK8.
Dardarin appears to contain a kinase domain, a RAS domain, a WD40 domain and a leucine-rich repeat. A 9Kb species seems to be predominant, though there may be splice variants. The authors confirmed that dardarin is expressed throughout adult human brain.
Does the presence of the kinase domain mean that dardarin could play a role in the phosphorylation of α-synuclein or tau? If this were true, the authors speculate, "[T]he description of myriad PARK8 pathological phenotypes ranging from pure nigral degeneration to pathologies with varied protein deposition, including synucleinopathy and tauopathy, is intriguing and these data raise the possibility that dardarin may present a link between these key molecules."— Hakon Heimer.
Paisan-Ruız C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Martınez Gil A, Khan N, Johnson J, Ruiz Martinez J, Nicholl D, Marti Carrera I, Saenz Pena A, de Silva R, Lees A, Martı-Masso JF, Perez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004 Nov 18;44(4):595-600. Abstract