Pdzd8-flox Mouse

PDZD8, the protein encoded by the PDZ domain containing 8 gene, has multiple essential functions. It acts as a tethering protein at the interfaces of different organelles, such as between the endoplasmic reticulum (ER) and mitochondria, ER and late endosome/lysosome, which is crucial for processes like Ca²⁺ dynamics regulation, lipid transfer, and organelle contact formation [2,3,4,6]. It is also involved in metabolic adaptation pathways, with the AMPK-PDZD8-GLS1 axis promoting glutaminolysis during glucose shortage [1].

In mouse models, PDZD8-KO mice show abnormal accumulation of cholesteryl esters in the brain due to impaired lipophagy, leading to growth retardation and behavioral abnormalities related to emotion, cognition, and adaptation [5]. In humans, homozygous premature termination codons in PDZD8 are associated with syndromic intellectual disability with autistic features. Similar cognitive deficits are replicated in Drosophila with knockdown of the PDZD8 ortholog and in Pdzd8 homozygous mutant mice, suggesting a conserved role in cognitive function [7]. In stress-induced hypertension rat models, reduced PDZD8 expression in the rostral ventrolateral medulla disrupts ER-mitochondria associations and mitochondrial functions, contributing to the disease pathology [8].

In summary, PDZD8 is vital for organelle-organelle interactions, lipid metabolism, and metabolic adaptation. Studies using gene knockout models in mice, flies, and rats have revealed its significance in cognitive development, emotional regulation, and blood pressure control, providing insights into the pathophysiology of related diseases.