Reelin Expression in Creutzfeldt-Jakob Disease and Experimental Models of Transmissible Spongiform Encephalopathies

Abstract

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration.

Disease-Specific Changes in Reelin Protein and mRNA in Neurodegenerative Diseases

“…With respect to sCJD, our data indicate a tendency to increased RELN and ≈420 kD Reelin expression in sCJD, reinforcing our previously published data [20] In addition, we used samples (brain samples and CSF) from two different biobanks: HUB-ICO-IDIBELL in and UMG in the present study, with similar results. Since RELN mRNA and protein levels in infective prion mouse models might occur only at the final stages of the disease, we believe that this change reflects the profound metabolic changes strongly present in the final stages of sCJD [20]. In addition, Reelin generated under these conditions is not functional, as it is in AD [18], which might enhance cognitive decline and disease progression.…”

“…A correlative study of the brain levels and CSF levels of Reelin in different neurodegenerative diseases is lacking. In a previous publication our group [20] developed a study to analyze the changes in RELN mRNA and protein levels in sporadic Creutzfeldt-Jakob disease (sCJD) postmortem samples [20]. In the present study, we expand on this to explore in detail the putative changes of full-length Reelin and RELN levels in post-mortem samples of neocortex and Reelin protein levels in CSF samples.…”