Protein phosphatase 1 regulatory subunit 21

Protein phosphatase 1 regulatory subunit 21 (PPP1R21) is a 780-amino acid scaffolding protein that functions as a core component of the FERRY complex, a five-subunit endosomal complex involved in mRNA localization and distribution (UniProt: Q6ZMI0). Within this complex, PPP1R21 acts as a binding hub connecting all five subunits and mediating interactions with mRNA and early endosomes through RAB5A, thereby regulating endosomal transport and mRNA recruitment to ribosomes. The protein may also serve as a putative regulator of protein phosphatase 1 activity and participate in endosomal sorting or maturation pathways.

UniProt curates a neurodevelopmental disorder association: pathogenic variants in PPP1R21 cause an autosomal recessive neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA; MIM 619383), characterized by developmental delay, intellectual disability, and structural brain changes including white matter abnormalities and cerebellar hypoplasia (UniProt: Q6ZMI0).

In Alzheimer's disease, PPP1R21 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2 fold-change: −0.83; Chaparral AD proteomics). This reduction may reflect impaired endosomal mRNA transport and ribosomal localization in AD pathology, potentially contributing to altered protein synthesis or metabolic dysfunction in degenerating neurons.