Transthyretin regulates lysosomal degradation of hippocampal 14–3‐3ζ

Abstract

Transthyretin (TTR) is a 55kDa homotetrameric protein mainly synthetized in liver and choroid plexus. It is the carrier protein of thyroxine and retinol in plasma and cerebrospinal fluid (CSF), and has also been shown to have neuroprotective properties both in the central and peripheral nervous system. Studies in TTR null mice (TTR−/−) revealed that absence of TTR reduces signs of depressive‐like behavior, increases neuropeptide Y levels, delay in nerve regeneration in nerve injury conditions; these mice present impaired memory when compared with wild type animals.14–3‐3 proteins very important in many cellular processes such as signal transduction, cell‐cycle regulation, cell survival, cellular trafficking, cytoskeletal organization, protein synthesis, redox‐regulation and protein folding. Their absence is also related with deficits in memory and learning. The analysis of the relationship between these two proteins is the main objective of this work. We found that hippocampus of young TTR null mice presented lower levels of 14–3‐3ζ protein, but no changes in gene expression when compared to TTR wild type littermates were noted. Cellular studies ascribed this finding to increased degradation of 14–3‐3ζ in lysosomes in the absence of TTR. Taken together, these results suggest that the lower levels of 14–3‐3ζ found in vitro and in vivo in the absence of TTR, are attributable to increased degradation in the lysosomal compartment. We hypothesize that the memory deficits found in TTR null mice might be relate to hippocampal 14–3‐3ζ deficiency.