Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

Abstract

Despite the complexity of neurodevelopmental disorders (NDDs), from their genotype to phenotype, in the last few decades substantial progress has been made in understanding their pathophysiology. Recent accumulating evidence shows the relevance of genetic variants in thousand and one (TAO) kinases as major contributors to several NDDs. Although it is well-known that TAO kinases are a highly conserved family of STE20 kinase and play important roles in multiple biological processes, the emerging roles of TAO kinases in neurodevelopment and NDDs have yet to be intensively discussed. In this review article, we summarize the potential roles of the TAO kinases based on structural and biochemical analyses, present the genetic data from clinical investigations, and assess the mechanistic link between the mutations of TAO kinases, neuropathology, and behavioral impairment in NDDs. We then offer potential perspectives from basic research to clinical therapies, which may contribute to fully understanding how TAO kinases are involved in NDDs.

Keywords: TAO kinase; cytoskeleton; de novo mutations; neurodevelopmental disorders; neuron; therapy.

Figure 1

Thousand and one (TAO) kinases are highly conserved. (A) Schematic structure of conserved TAO kinase family is shown. A typical protein structure of TAO kinase includes a catalytic domain, a central domain, and a regulatory domain, which could regulate catalytic activity. In humans, three genes of TAO kinases encoding TAO1, TAO2, and TAO3 are present, each of them has two isoforms (α and β, except TAO2 has the third putative one γ isoform) which may take different biological functions. Only a single Tao gene is encoded in Drosophila melanogaster (CG14217, Tao) and C. elegans (kin-18). (B) The relative expression levels (TPM) of human TAO kinases in different areas of the central nervous system (CNS) are shown. The bar represents the median value from RNA sequencing. Data source: the Genotype-Tissue Expression (GTEx) project. M, male; F, female.

Figure 2

General functions of TAO kinases in regulation of cytoskeletal dynamics and mitogen activated protein kinase (MAPK) cascade cytoskeletal dynamics. See the main text for details. Note that TAO1 and TAO2 share similar functions, although TAO1 preferentially activates p38 and TAO2 preferentially activates JNK. Importantly, the possible distinct function between TAO3 and TAO1/2 should be further examined.

Figure 3

Molecular mechanisms of Tao kinases in neurodevelopment. TAO2 could regulate dendrite development (blue labeled) and spine development (yellow labeled) with multiple signaling pathways. In Drosophila, Tao kinase regulated dendritic development is also indicated with an unknown upstream pathway [?-pTao-Microtubule (MT)/actin] (purple labeled). In addition, TAO2 functions downstream of BDNF to activate the JNK signaling cascade to regulate interneuron maturation during development. However, whether TAO kinases contribute to axonal development and the underlying mechanisms remains to be determined. See details in the main text.

Figure 4

Perspectives on developing potential therapies for TAO kinases mutations caused neurodevelopmental disorders (NDDs). Current therapies include most symptomatic and behavioral based treatments which could be applied to all factors caused NDDs including traditional clinical training, medical treatment, nutritional supplementation, and brain stimulations. With significant progress in biotechnology, the concept for future therapies could focus on personalized therapy by specifically targeting TAO kinase mutations by gene therapy, developing specific agonist or inhibitors and rewiring neural circuits with chemo- or optogenetics.