Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

Abstract

Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may bring therapeutic advances. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome (TS), autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Here, we systematically review the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in TS and other neurodevelopmental traits. Such findings highlight Ash1l pleiotropy and the necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases. With the progress in functional genomic analysis (highlighted in this review), and although the importance and necessity of Ash1l becomes increasingly apparent in the medical field, further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross‐disorder diseases.

Counteracting epigenetic mechanisms regulate the structural development of neuronal circuitry in human neurons

“…1F ), compared to control transfected neurons, with no significant differences between the different ASH1L shRNA transfected neurons. In published mouse models of ASH1L deficiency, the reduction in ASH1L levels in heterozygous animals is between 50 to 60% 38 , 41 , 42 . While defects in neuronal excitability were reported in one study 42 to date, no major brain anatomical phenotypes have been reported in published studies of heterozygous animals 38 , 41 , 42 .…”

Tourette syndrome research highlights from 2020

“…2017 ). A review by Zhang and colleagues highlighted the possible role of variants in ASH1 Like Histone Lysine Methyltransferase ( ASH1L) in the etiology of psychiatric disorders including TS, autism spectrum disorders and intellectual disability ( Zhang et al . 2021 ).…”

Overcoming the effect of ASH1L haploinsufficiency on stem cells amenability to genome editing and differentiation into the neuronal lineage – a technical report

“…Since mutations in ASH1L have previously been associated with several neurological disorders, including ASD [15,17], Attention-deficit/hyperactivity disorder [46], and Tourette syndrome [47,48], we tested the viability of our mutant ASH1L ESCs for neuronal induction. Our lab routinely uses a dual-SMAD inhibition protocol that leads to the generation of excitatory cortical neurons [29].…”