Abstract
BackgroundProgressive 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.MethodsTo 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.ResultsWe 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.ConclusionsOur findings suggest a possible etiology for the two most common FTLD subtypes through a kinase activation driven mechanism of neurodegeneration.
Highlights
Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD)
Human TTBK1 and TTBK2 kinase domain transgenic C. elegans are behaviorally normal To understand whether TTBK1 and TTBK2 kinases play a direct role in neurodegeneration, we constructed transgenic (Tg) C. elegans lines expressing kinase catalytic domains of human TTBK1 or TTBK2 under the pan-neuronal promoter rgef-1 by micro-injecting a plasmid transgene (Prgef-1::hTTBK1 and Pregef-1::hTTBK2)
TTBK1 levels are elevated in both FTLD-tau and FTLD-with TDP-43 pathology (TDP) We have demonstrated in C. elegans that catalytically active TTBK1 and TTBK2 promote tau and TDP-43 phosphorylation [9]
Summary
Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). 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. Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease clinically diagnosed by evidence of personality and behavioral changes and language dysfunction [1]. Phosphorylated tau has been implicated in the formation of toxic tau aggregates that promote neurodegeneration [10,11,12,13,14,15]
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