NDE1 and NDEL1 from genes to (mal)functions: parallel but distinct roles impacting on neurodevelopmental disorders and psychiatric illness

Abstract

NDE1 (Nuclear Distribution Element 1, also known as NudE) and NDEL1 (NDE-Like 1, also known as NudEL) are the mammalian homologues of the fungus nudE gene, with important and at least partially overlapping roles for brain development. While a large number of studies describe the various properties and functions of these proteins, many do not directly compare the similarities and differences between NDE1 and NDEL1. Although sharing a high degree structural similarity and multiple common cellular roles, each protein presents several distinct features that justify their parallel but also unique functions. Notably both proteins have key binding partners in dynein, LIS1 and DISC1, which impact on neurodevelopmental and psychiatric illnesses. Both are implicated in schizophrenia through genetic and functional evidence, with NDE1 also strongly implicated in microcephaly, as well as other neurodevelopmental and psychiatric conditions through copy number variation, while NDEL1 possesses an oligopeptidase activity with a unique potential as a biomarker in schizophrenia. In this review, we aim to give a comprehensive overview of the various cellular roles of these proteins in a "bottom-up" manner, from their biochemistry and protein-protein interactions on the molecular level, up to the consequences for neuronal differentiation, and ultimately to their importance for correct cortical development, with direct consequences for the pathophysiology of neurodevelopmental and mental illness.

DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis

“…Nde1 and Ndel1 paralogues have been previously studied and show similar behaviors in cell cycle in non-neuronal cells (Stehman et al, 2007). Recently, it was found Nde1 and Ndel1 can substitute each other in many aspects of neurogenesis and neuronal migration (Bradshaw and Hayashi, 2017) . However, Nde1 also displays its unique roles in the cell cycle progression of radial glial progenitors (Doobin et al, 2016).…”

Mechanisms underlying the role of DISC1 in synaptic plasticity

“…) and its accessory proteins NDE1 and NDEL1 (Cianfrocco et al . ; Bradshaw & Hayashi, ). The DISC1 interactor and cAMP phosphodiesterase PDE4 also interacts with LIS1 (Murdoch et al .…”

Genetics and mechanisms leading to human cortical malformations

“…Mutations of this gene were found in patients with very severe form of microcephaly, ACC and fetal brain disruption (FBD)-like cortical malformation, profound ID and early onset seizures [78,264]. The effect of NDE1 on cortical thickness is due to alterations in neuronal progenitor fate [80].…”

“…Particularly, the loss of NDE1 increases the number of differentiated PP cortical neurons and Cajal-Retzius cells which are produced during early corticogenesis, depleting the neuroepithelial cells and RGC pool for neuron production at later stages of development. This is a consequence of failures in the assembly and orientation of the mitotic spindle which requires NDE1 function [77,80,264]. On the other hand, loss of its paralogue NDEL1 prevents the migration of neurons into the CP, although the motility within the IZ or SVZ is not affected [264,265].…”

“…This is a consequence of failures in the assembly and orientation of the mitotic spindle which requires NDE1 function [77,80,264]. On the other hand, loss of its paralogue NDEL1 prevents the migration of neurons into the CP, although the motility within the IZ or SVZ is not affected [264,265]. NDE1 mutations also give rise to rare cases of PMG, it remains unclear how this arises, but RGC perturbations are also likely to affect basal endfeet attachment at the BM.…”