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

Pathological aggregates of phosphorylated tdp-43 characterize amyotrophic lateral sclerosis (als) and frontotemporal lobar degeneration (ftld-tdp),two devastating groups of neurodegenerative disease. kinase hyperactivity may be a consistent feature of als and ftld-tdp,as phosphorylated tdp-43 is not observed in the absence of neurodegeneration. by examining changes in tdp-43 phosphorylation state,we have identified kinases controlling tdp-43 phosphorylation in a c. elegans model of als. in this kinome-wide survey,we identified homologs of the tau tubulin kinases 1 and 2 (ttbk1 and ttbk2),which were also identified in a prior screen for kinase modifiers of tdp-43 behavioral phenotypes. using refined methodology,we demonstrate ttbk1 and ttbk2 directly phosphorylate tdp-43 in vitro and promote tdp-43 phosphorylation in mammalian cultured cells. ttbk1/2 overexpression drives phosphorylation and relocalization of tdp-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states. furthermore,protein levels of ttbk1 and ttbk2 are increased in frontal cortex of ftld-tdp patients,and ttbk1 and ttbk2 co-localize with tdp-43 inclusions in als spinal cord. these kinases may represent attractive targets for therapeutic intervention for tdp-43 proteinopathies such as als and ftld-tdp. © 2014.