Abstract
Both genetic and environmental factors contribute to the development of intellectual disability (ID). Previously, we identified a promoter variant (-113C>A) in PLP2 (proteolipid protein 2) that results in an ∼4-fold reduction of transcript and protein and is overly represented in males with X-linked ID (XLID). The functional connection between reduced PLP2 expression and increased risk to XLID is unknown. To investigate the pathophysiological mechanisms, we studied a Plp2-loss-of-function murine model and fibroblasts from XLID patients hemizygous for PLP2-(-113C>A). We found that Plp2-deficient mouse embryonic fibroblast and human fibroblasts carrying PLP2-(-113C>A) have similarly defective endoplasmic reticulum (ER) trafficking, increased basal ER stress and exaggerated susceptibility to inducers of ER stress. Plp2-deficient mice show increased neuronal death to ER stress and hypoxia in vitro and in a neonatal hypoxia-ischemia model in vivo. Finally, we provide evidence that up-regulation of PLP2 directly promotes resistance to ER stressors. Results of our studies support the hypothesis that reduced PLP2 expression increase susceptibility of neurons to environmental ER stressors such as hypoxia and ischemia and that increased apoptosis and neuronal death contribute to the risks to ID in humans.