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.

Proteomic Identification of Phosphorylation-Dependent Septin 7 Interactors that Drive Dendritic Spine Formation

“…Recently, we discovered that TAOK2α is an endoplasmic reticulum–associated kinase with a transmembrane C-terminal region ( Nourbakhsh et al, 2021 ). Given the structural conservation among the kinase domain of TAO kinases and their high expression in the brain ( Hu et al, 2021 ), we tested whether closely related kinase TAOK1 and the alternatively spliced isoforms of TAOK2, TAOK2α, and TAOK2β could also phosphorylate Sept7 at T426. GFP-tagged TAOK1, TAOK2α, and TAOK2β were expressed independently in HEK293T cells, immuno-precipitated using GFP antibody and then incubated with purified GST-Septin7 protein ( Supplementary Figure S1B ) in an in vitro kinase reaction.…”

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

“…On the other hand, in early adulthood, the expression of Mecp2 and Setd1b was increased in males from the HFD group, and the Pten and Fmr1 mRNA levels in females from all groups (HFD, HCD, and MD) were decreased. Expression changes as well as mutations in genes whose mRNA levels were disturbed by the maternal diet were noted in patients with ASD in various brain structures that are important in the pathogenesis of this disorder [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. It is worth emphasizing that ASD-associated genes, including genes whose proper expression was disturbed by the maternal diet, are characterized by functional pleiotropy and are crucial for proper brain development in the early stages and subsequent brain functioning.…”

Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities

“…The TAO kinase family consists of three genes, TAOK1 , TAOK2 , and TAOK3 , which encode TAOK1, TAOK2, and TAOK3, respectively ( Dan et al, 2001 ; Miller et al, 2019 ). TAO kinases play multifunctional roles in many molecular and cellular events and can regulate neuronal survival and development in the nervous system ( Fang et al, 2020 ; Hu et al, 2021 ). TAOK1 is highly expressed in the human brain and plays a role in the establishment of neuronal polarity, neuronal differentiation, and early brain development ( Biernat et al, 2002 ; Timm et al, 2006 ; Draviam et al, 2007 ; Breuss and Keays, 2014 ; Poon et al, 2016 ).…”