Exploring the molecular and cellular mechanism(s) underlying neurodevelopmental disorders: investigating the role(s) of Nuclear Distribution Element like-1 (Ndel1)

Abstract

Over the past few years, Hayashi's lab has identified a couple of potential biomarkers to support the diagnosis of mental disorders (MDs), such as schizophrenia (SCZ) and bipolar disorder (BD), while also working on the nuclear distribution element-like 1 (Ndel1) oligopeptidase activity as a potential biomarker for diagnosis and/or treatment response in SCZ. The importance of Ndel1 for neuritogenesis and neuronal migration during embryogenesis and brain formation has been extensively demonstrated by several in vitro and in vivo models. In addition, a significantly lower Ndel1 activity was reported in plasma of patients with SCZ and BD compared to healthy controls with a correlation between Ndel1 activity decreases and symptoms amelioration in first-episode psychosis under treatment. Several MDs, including SCZ, can arise due to neurodevelopmental deficits, also sharing symptoms with recognized neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although our previous studies may have contributed to identifying pathways related to the pathophysiology of SCZ, it was not possible to identify the determining molecular and/or cellular mechanism(s) underlying mental disorders, mainly due to the lack of a good model for different stages of human neurodevelopment. Therefore, we propose a biochemical, molecular, and cellular evaluation using brain organoids derived from iPSCs to model human neurodevelopment in physiological and pathological conditions, exploring the etiology of neuropathological diseases. This study may also contribute to further evaluating the Ndel1 enzyme activity and proteostasis in the context of different neurodevelopmental disorders involving possible neuronal dynamics. This knowledge may contribute to clarifying the real potential of Ndel1 as a target protein for reverting or preventing abnormal phenotypes associated with increased susceptibility to developing brain disorders. (AU)