Schizophrenia (SCZ) is a devastating chronic mental disease determined by genetic and environmental factors, which susceptibility may involve an impaired neural migration during the neurodevelopmental process. Several candidate risk genes potentially associated with SCZ were related to the formation of
protein complexes that ultimately mediate alterations in the neuroplasticity. The most studied SCZ risk gene is the Disrupted-in-
Schizophrenia 1 (DISC1) gene, which functions seem to depend on the binding with cytoskeleton
proteins, as the Nuclear-distribution gene E homolog like-1 (Ndel1)
protein among others. Interestingly, Ndel1 is the only binding partner of DISC1
proteins with
oligopeptidase activity, besides playing roles in multiple processes, including cytoskeletal organization, cell signaling, neuron migration, and neurite outgrowth. It is still not clear if the
protein-
protein interaction between Ndel1 and DISC1 is enough to explain all cellular functions attributed to these
proteins, but there are several lines of evidence suggesting the importance of the catalytic activity of Ndel1 for the neurite outgrowth and neuron migration during embryogenesis. Recent works of the group have demonstrated the modulation of Ndel1 activity by DISC1, which is hypothetically impaired in SCZ patients. In fact, more recently, we also showed a lower Ndel1 activity in the plasma of SCZ patients compared to control health subjects, but the physiopathological significance of this feature is still unknown. Here we discuss Ndel1
ligands involved in
protein-
protein complex formations related to neurodevelopmental diseases, as (
1) lissencephaly or
Miller-Dieker Syndrome (MDS), which is characterized by the typical craniofacial features and abnormal smooth cerebral surface, and
as (2) SCZ, since they both seem to be determined by defects in neuronal migration. Although impaired
lissencephaly protein Lis1 complex formation with Ndel1 is the leading cause of
lissencephaly, this binding does not affect Ndel1
oligopeptidase activity. On the other hand, although MDS and SCZ may be both determined by an abnormal neuronal migration, DISC1 complex formation with Ndel1 was shown to inhibit Ndel1 activity. Also differently of MDS, SCZ needs inputs from environmental factors, while
lissencephaly is not likely dependent or affected by the environment. Several other
proteins and
peptide ligands were described for Ndel1, Lis1 and DISC1, thanks to the employment of biochemical, immunochemical, and
biological (using cells or living animals) assays, including heterologous expression and also simply by purification from nature of these
proteins in the complex form. Effects of the post-translational modifications of these
proteins are also discussed here. Taken together, the data presented here show in essence how
protein-
protein and proteinpeptide interactions can underlie fundamental processes as cell division, maturation and migration, necessary for adequate formation of a complex structured tissue as the brain. A special attention was given to Ndel1 as this
protein binds to either
proteins or
peptides, besides having proteolytic activity. Moreover, Ndel1 seems to be the key
protein underlying two seemingly unrelated diseases with highly complex etiology, as
lissencephaly and SCZ.