Phosphofurin acidic cluster sorting protein 2

PACS2 (phosphofurin acidic cluster sorting protein 2) is a multifunctional sorting protein that regulates endoplasmic reticulum (ER)-mitochondria communication and cellular apoptosis (UniProt: Q86VP3). It controls the apposition of mitochondria with the ER, maintains ER homeostasis, and directs pro-apoptotic factors like BID to mitochondria during stress responses. The protein also participates in ion channel trafficking to distinct subcellular compartments.

PACS2 is implicated in developmental and epileptic encephalopathy 66 (DEE66), a severe early-onset autosomal dominant epilepsy with refractory seizures and neurodevelopmental impairment (UniProt: Q86VP3). The protein's central role in ER-mitochondrial dynamics and apoptotic regulation positions it within pathways critical for neuronal function and survival.

In Alzheimer's disease, PACS2 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.567 (Chaparral AD proteomics). This downregulation across subcellular fractions suggests potential impairment of ER-mitochondrial communication and apoptotic control in AD pathology, though the functional consequences require further investigation.