Great Expectations: Induced pluripotent stem cell technologies in neurodevelopmental impairments

Oliveira

et al. 2023

IJMS

Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.

Section: Resultsmentioning

confidence: 99%

A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia

Oliveira

et al. 2023

IJMS

“…The studies of epigenetics, neuroimmunology, and neurobiology in ASD indicated that cell therapy was an effective approach for treating the core symptoms of ASD ( Vaccarino et al, 2011 ; Siniscalco et al, 2012b ; Liu et al, 2019 ; Zhang et al, 2021 ). Two outstanding features of stem cells are the intense immunosuppressive activity that allows them to be used in autologous or heterologous transplantation ( Siniscalco et al, 2012a ) and paracrine actions ( Baraniak and McDevitt, 2010 ; Siniscalco, 2012 ).…”

Section: Treatment and Intervention Of Repetitive Restricted Behaviorsmentioning

confidence: 99%

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

2022

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.

“…First, the neurobiological functions of TAO kinases should be further investigated. At the molecular level, identification of specific up- and down-stream substrates for TAO kinases in different model systems, especially by combining human induced pluripotent stem cell (iPSC) from patients, is crucial for a better understanding of the mechanisms leading to the onset of a disease-phenotype (Parenti et al, 2020 ; Zhang et al, 2020 ). At cellular level, previous reports focus on the cell-autonomous role of TAO kinases in regulating the development of dendrites and dendritic spines.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

Pan

Yang

et al. 2021

Front. Mol. Neurosci.

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.