14-3-3 protein zeta/delta

14-3-3 protein zeta/delta (YWHAZ) is an adapter protein that regulates diverse signaling pathways by binding phosphorylated partners, typically resulting in modulation of their activity (UniProt: P63104). It promotes cytosolic retention of the TFEB transcription factor and modulates neuronal spine maturation through regulation of ARHGEF7 activity. The protein is implicated in Popov-Chang syndrome, an autosomal dominant developmental disorder characterized by global developmental delay, intellectual impairment, speech deficits, and behavioral features including autistic-like behavior (UniProt: P63104).

In Alzheimer's disease, 14-3-3 zeta/delta is significantly down-regulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.88 (Chaparral AD proteomics). This reduction was observed across subcellular fractions in TMT-labeled proteomic analysis. The decreased abundance of this signaling adapter in AD brain may reflect disrupted cellular signaling and protein trafficking mechanisms implicated in neurodegeneration.