2. Academic Validation
  3. Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration

Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration

  • Mol Neurodegener. 2018 Feb 6;13(1):7. doi: 10.1186/s13024-018-0237-9.
Laura M Taylor 1,  Pamela J McMillan 2,  Nicole F Liachko 1 3,  Timothy J Strovas 1,  Bernardino Ghetti 4,  Thomas D Bird 1 5 6,  C Dirk Keene 7,  Brian C Kraemer 8 9 10 11
Affiliations

Affiliations

  • 1 Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA.
  • 2 Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 98195, USA.
  • 3 Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
  • 4 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • 5 Department of Neurology, University of Washington, Seattle, WA, 98195, USA.
  • 6 Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
  • 7 Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
  • 8 Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA, 98108, USA. kraemerb@u.washington.edu.
  • 9 Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA. kraemerb@u.washington.edu.
  • 10 Department of Neurology, University of Washington, Seattle, WA, 98195, USA. kraemerb@u.washington.edu.
  • 11 Department of Pathology, University of Washington, Seattle, WA, 98195, USA. kraemerb@u.washington.edu.
PMID: 29409526 DOI: 10.1186/s13024-018-0237-9
Abstract

Background: Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients. Both TTBK1 and TTBK2 were initially identified as tau kinases and TTBK1 has been shown to phosphorylate tau epitopes commonly observed in Alzheimer's disease and Other tauopathies.

Methods: To further elucidate how TTBK1/2 activity contributes to both TDP-43 and tau phosphorylation in the context of the neurodegeneration seen in FTLD, we examined the consequences of elevated human TTBK1/2 kinase expression in transgenic animal models of disease.

Results: We show that C. elegans co-expressing tau/TTBK1 tau/TTBK2, or TDP-43/TTBK1 transgenes in combination exhibit synergistic exacerbation of behavioral abnormalities and increased pathological protein phosphorylation. We also show that C. elegans co-expressing tau/TTBK1 or tau/TTBK2 transgenes in combination exhibit aberrant neuronal architecture and neuron loss. Surprisingly, the TTBK2/TDP-43 transgenic combination showed no exacerbation of TDP-43 proteinopathy related phenotypes. Additionally, we observed elevated TTBK1/2 protein expression in cortical and hippocampal neurons of FTLD-tau and FTLD-TDP cases relative to normal controls.

Conclusions: Our findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration.

Keywords

C. elegans; Frontotemporal lobar degeneration; Neurodegeneration; TDP-43; TTBK1; TTBK2; Tau.

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