3 December 2007. Mutations in a tau kinase gene have been tied to the neurodegenerative disease spinocerebellar ataxia type 11 by British researchers Henry Houlden and Nicholas Wood at the Institute of Neurology in London. The work, published online in Nature Genetics on November 25, identifies mutations in tau tubulin kinase 2 (TTBK2) in two families with the autosomal-dominant disease, and shows tau deposition and cell loss in affected brain areas in one affected member. Mutations in the gene for tau, MAPT, cause frontotemporal dementias, but this is the first time that a tau regulator has been linked to disease, and the first time tau regulation or deposition has been implicated in any form of SCA.
The researchers identified the mutations in two families with a history of SCA linked to chromosome 15 q14-21. Both mutations introduced premature stop codons, and affected people had a 50 percent reduction in TTBK2 messenger RNA. Brain tissue from a patient showed neurofibrillary tangles and other tau pathology, as well as amyloid plaques in some regions of the brain. Cortical tau lesions are common in aged brain, but the authors note that they also found tau in regions not normally affected by aging, namely, the basal ganglia, midbrain, and medulla. In the cerebellum, the scientists saw cell loss but no tau pathology.
TTBK2 loss has previously been linked to a tau-induced movement disorder, at least in worms. Knockdown of the kinase enhanced the uncoordinated movement phenotype of a C. elegans strain expressing a mutant tau transgene (Kraemer et al., 2006). Clarifying the link between TTBK2 mutations and tau pathology will require further analysis of brain tissue from additional affected individuals, the authors write.—Pat McCaffrey.
Houlden H, Johnson J, Gardner-Thorpe C, Lashley T, Hernandez D, Worth P, Singleton AB, Hilton DA, Holton J, Revesz T, Davis MB, Giunti P, Wood NW. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet. 2007 Dec;39(12):1434-6. Epub 2007 Nov 25. Abstract