Reelin is a protein that has been consistently found to be decreased in brains in postmortem studies of patients with schizophrenia, thus I’ve been tracking it for years on PubMed
A curious new study shows that a (small?) protein construct may negate the effects of decreased reelin levels. I’m hoping for the creation of a molecule that could be deliverable into the brain. Thus far, though, it was delivered by direct injection into brain ventricles, which is not feasible in human. But I hope that each such work/discovery makes a step forward. Maybe there’ll be other ways for activating the same pathway, and new constructs will make it easier for scientists to look for such ways.
# A novel Reelin construct, R36, recovered behavioral deficits in the heterozygous reeler mouse
Reelin, a large extracellular glycoprotein, plays a critical role in prenatal brain development and postnatally in synaptic plasticity, learning and memory. Dysregulation of Reelin signaling has been implicated in several neuropsychiatric disorders including schizophrenia, autism, depression, and Alzheimer’s disease. Previous studies have demonstrated that Reelin’s central fragment, R3456, binds to ApoER2, inducing ApoER2 clustering and subsequent intracellular signaling. We previously reported the development of a novel luciferase complementation assay which we used to demonstrate that R3456 can lead to ApoER2 receptor dimerization. Using this same assay, we explored various smaller fragments and combinations from R3456, and we identified a construct of repeats 3 and 6 (R36) which could still elicit equivalent receptor dimerization. The purpose of this study was to test R36 for biological effects in vitro and in vivo. We show that R36 was capable of initiating intracellular signaling in primary neuronal cultures. In addition, we demonstrate that a single intracerebroventricular injection of R36 protein into a model of Reelin deficiency, the heterozygous reeler mice can significantly improve cognition. These data support a role for the new construct R36 to enhance the Reelin pathway and the future possibility of exploring gene therapy approaches with R36 in diseases characterized by reduced levels of Reelin.