The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43

• DOI: 10.1371/journal.pgen.1004803
• Publication Date: 2014-12-04T19:31:15Z
• Authors: Nicole F. Liachko; Pamela J. McMillan; Timothy J. Strovas; Elaine Loomis; Lynne Greenup; Jill R. Murrell; Bernardino Ghetti; Murray A. Raskind; Thomas J. Montine; Thomas D. Bird; James B. Leverenz; Brian C. Kraemer
• Keywords: Kinome; Frontotemporal lobar degeneration

Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups neurodegenerative disease. Kinase hyperactivity may be a consistent feature ALS FTLD-TDP, as is not observed in the absence neurodegeneration. By examining changes phosphorylation state, we have identified kinases controlling C. elegans model ALS. In this kinome-wide survey, homologs tau tubulin 1 2 (TTBK1 TTBK2), which were also prior screen for kinase modifiers behavioral phenotypes. Using refined methodology, demonstrate TTBK1 TTBK2 directly phosphorylate vitro promote mammalian cultured cells. TTBK1/2 overexpression drives relocalization from nucleus to cytoplasmic inclusions reminiscent neuropathologic disease states. Furthermore, protein levels are increased frontal cortex FTLD-TDP patients, co-localize with spinal cord. These represent attractive targets therapeutic intervention proteinopathies such FTLD-TDP.