Tau tubulin kinases in proteinopathy

Abstract

A number of neurodegenerative diseases are characterized by deposition of abnormally phosphorylated tau or TDP-43 in disease-affected neurons. These diseases include Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. No disease-modifying therapeutics is available to treat these disorders, and we have a limited understanding of the cellular and molecular factors integral to disease initiation or progression. Phosphorylated tau and TDP-43 are important markers of pathology in dementia disorders and directly contribute to tau- and TDP-43-related neurotoxicity and neurodegeneration. Here, we review the scope of tau and TDP-43 phosphorylation in neurodegenerative disease and discuss recent work demonstrating the kinases TTBK1 and TTBK2 phosphorylate both tau and TDP-43, promoting neurodegeneration.

Keywords: ALS; CBD; FTLD; PSP; Alzheimer's disease; Pick's disease; TDP-43; TTBK1; TTBK2; phosphorylation; tau; tauopathy.

Fig. 1.

Frontotemporal lobar degeneration-tau and FTLD-TDP-43 exhibit increased TTBK1 and TTBK2. (A) tau neuropathology stained with AT8 (tau pS02/pS205) from frontal cortex of an FTLD case. (B) TDP-43 neuropathology stained with pS409/pS410 TDP-43 antibody from frontal cortex of an FTLD-TDP case. (C, D) TTBK1 kinase domain-specific staining in frontal cortex of FTLD-tau and FTLD-TDP cases respectively. (E, F) TTBK2 kinase domain-specific staining in frontal cortex of FTLD-tau and FTLD-TDP cases respectively. Scale bar = 100 μM.

Fig. 2.

Tau tubulin kinase 1 phosphorylates tau and TDP-43 in disease-state neurons. In healthy neurons (top), TTBK1 promotes the formation of synapses and neuronal development. TTBK1 likely has additional unknown roles in the central nervous system. Dysregulated TTBK1 kinase activities (bottom) can promote pathological phosphorylation of tau or TDP-43 and subsequent disease.

Fig. 3.

Tau tubulin kinase 2 phosphorylates tau but not TDP-43 in disease-state neurons. In healthy neurons (top), TTBK2 regulates Na+ -coupled transporters, ciliogenesis, and neuronal maturation. Dysregulated TTBK2 kinase activities (bottom) can promote pathological phosphorylation of tau and subsequent disease.

Fig. 4.

Protein domains of TTBK1 and TTBK2. (A) The longest isoform of TTBK1 protein has an N-terminal kinase domain and two regulatory domains (Domain A and Domain B) separated by 39 amino acid polyglutamine stretch. (B) The longest isoform of TTBK2 has an N-terminal kinase domain and a C terminus with no homology to known protein domains. The sites of familial-inherited SCA11-causing frameshift mutations are labeled.