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The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.

Liachko NF, McMillan PJ, Strovas TJ, Loomis E, Greenup L, Murrell JR, Ghetti B, Raskind MA, Montine TJ, Bird TD, Leverenz JB, Kraemer BC - PLoS Genet. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

TTBK1/2 co-localize with phosphorylated TDP-43 in ALS spinal cord aggregates.Double-label immunofluorescence of ALS spinal cord of (A) TTBK1 and (B) TTBK2 show significant co-localization of TTBK1/2 with phospho-TDP-43 within neuronal cytoplasmic inclusions. Significance was determined using Pearson coefficient of colocalization.
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pgen-1004803-g006: TTBK1/2 co-localize with phosphorylated TDP-43 in ALS spinal cord aggregates.Double-label immunofluorescence of ALS spinal cord of (A) TTBK1 and (B) TTBK2 show significant co-localization of TTBK1/2 with phospho-TDP-43 within neuronal cytoplasmic inclusions. Significance was determined using Pearson coefficient of colocalization.

Mentions: Of the six ALS cases examined, only two had phospho-TDP-43 aggregates in the frontal cortex and hippocampus, while all six demonstrated phospho-TDP-43 aggregates within spinal cord. ALS spinal cord motor neurons immunoreactive for phospho-TDP-43 pathology also co-labeled with TTBK1 and TTBK2 (Fig. 5A, B). Of the two ALS cases with pathologic changes in brain, a subset of neurons in the hippocampus and frontal cortex containing phospho-TDP-43 aggregates also co-expressed TTBK1 and TTBK2, while other neurons appeared to be immunoreactive for phospho-TDP-43 alone (Fig. 5 C–H). To test whether TTBK1/2 co-localize with phosphorylated TDP-43, we performed double-label immunofluorescence on ALS spinal cord sections (Fig. 6 and S8 Figure). In general, more neurons were immunofluorescent for TTBK1/2 than for phosphorylated TDP-43. Similar to our double label immunohistochemical data, neurons immunofluorescent for phosphorylated TDP-43 usually co-localized with TTBK1/2, although some neurons labeled with phosphorylated TDP-43 alone. Taken together Figs. 4, 5 and 6 repeatedly demonstrate an overlapping expression pattern for TTBK1/2 and pS409/410 TDP-43 inclusions in ALS and FTLD-TDP consistent with TTBK1/2 participation in the genesis of TDP-43 lesions.


The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.

Liachko NF, McMillan PJ, Strovas TJ, Loomis E, Greenup L, Murrell JR, Ghetti B, Raskind MA, Montine TJ, Bird TD, Leverenz JB, Kraemer BC - PLoS Genet. (2014)

TTBK1/2 co-localize with phosphorylated TDP-43 in ALS spinal cord aggregates.Double-label immunofluorescence of ALS spinal cord of (A) TTBK1 and (B) TTBK2 show significant co-localization of TTBK1/2 with phospho-TDP-43 within neuronal cytoplasmic inclusions. Significance was determined using Pearson coefficient of colocalization.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4256087&req=5

pgen-1004803-g006: TTBK1/2 co-localize with phosphorylated TDP-43 in ALS spinal cord aggregates.Double-label immunofluorescence of ALS spinal cord of (A) TTBK1 and (B) TTBK2 show significant co-localization of TTBK1/2 with phospho-TDP-43 within neuronal cytoplasmic inclusions. Significance was determined using Pearson coefficient of colocalization.
Mentions: Of the six ALS cases examined, only two had phospho-TDP-43 aggregates in the frontal cortex and hippocampus, while all six demonstrated phospho-TDP-43 aggregates within spinal cord. ALS spinal cord motor neurons immunoreactive for phospho-TDP-43 pathology also co-labeled with TTBK1 and TTBK2 (Fig. 5A, B). Of the two ALS cases with pathologic changes in brain, a subset of neurons in the hippocampus and frontal cortex containing phospho-TDP-43 aggregates also co-expressed TTBK1 and TTBK2, while other neurons appeared to be immunoreactive for phospho-TDP-43 alone (Fig. 5 C–H). To test whether TTBK1/2 co-localize with phosphorylated TDP-43, we performed double-label immunofluorescence on ALS spinal cord sections (Fig. 6 and S8 Figure). In general, more neurons were immunofluorescent for TTBK1/2 than for phosphorylated TDP-43. Similar to our double label immunohistochemical data, neurons immunofluorescent for phosphorylated TDP-43 usually co-localized with TTBK1/2, although some neurons labeled with phosphorylated TDP-43 alone. Taken together Figs. 4, 5 and 6 repeatedly demonstrate an overlapping expression pattern for TTBK1/2 and pS409/410 TDP-43 inclusions in ALS and FTLD-TDP consistent with TTBK1/2 participation in the genesis of TDP-43 lesions.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus