Gamma-adducin

Gamma-adducin (ADD3) is a membrane-cytoskeleton-associated protein that promotes assembly of the spectrin-actin network and plays roles in actin filament capping and regulation of the actin cytoskeleton (UniProt: Q9UEY8). It binds calmodulin and is involved in myogenic reactivity of vascular and renal tissues, regulating potassium channels and controlling expression of cytoskeletal and adhesion proteins such as synaptopodin, integrins, and nephrin. The protein also promotes neurite growth.

ADD3 has been associated with cerebral palsy, spastic quadriplegic 3 (CPSQ3; MIM 617008), an autosomal recessive neurodevelopmental disorder characterized by spasticity and cognitive impairment (UniProt: Q9UEY8). Beyond this genetic link, the protein's roles in actin dynamics and cell adhesion are relevant to neuronal function more broadly.

In Alzheimer's disease, ADD3 is significantly upregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of 0.53 across one fraction in a TMT-labeled proteomics study of four subcellular compartments (Chaparral AD proteomics). This upregulation may reflect altered cytoskeletal dynamics or compensatory responses in the degenerating AD brain.