title: The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.
abstract: 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.
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Liachko
authors.affiliation: Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McMillan
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Strovas
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Elaine
authors.initials: E
authors.lastname: Loomis
authors.affiliation: Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Lynne
authors.initials: L
authors.lastname: Greenup
authors.affiliation: Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Murrell
authors.affiliation: Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America; Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Murray A
authors.initials: MA
authors.lastname: Raskind
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, United States of America; Parkinson's Disease Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Neurology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States of America; Department of Neurology, University of Washington, Seattle, Washington, United States of America; Parkinson's Disease Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis; D034622:RNA Interference
chemical_list: D004268:DNA-Binding Proteins; C095903:tau-tubulin kinase; D017346:Protein Serine-Threonine Kinases