Abstract
SummaryDerlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function.
Highlights
To prevent misfolding of proteins and ensuing pathological endoplasmic reticulum (ER) stress, cells activate the unfold protein response (UPR), which restores ER protein homeostasis by refolding or degrading unfolded proteins
Reduced neurite outgrowth due to Derlin family members (Derlins)-1 deficiency was rescued by sterol regulatory element binding protein 2 (SREBP-2) pathway activation
Our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function
Summary
To prevent misfolding of proteins and ensuing pathological endoplasmic reticulum (ER) stress, cells activate the unfold protein response (UPR), which restores ER protein homeostasis by refolding or degrading unfolded proteins. Derlins contribute to ER protein quality control by facilitating the degradation of newly synthesized ER-targeted proteins, termed ER stress-induced pre-emptive quality control (ERpQC) (Kadowaki et al, 2015, 2018). Unlike Derlin-1- or Derlin-2-deficient mice, Derlin-3-deficient mice are normally born and grow as well as wild-type mice (Eura et al, 2012). We have reported that the interactions of Derlin-1 with amyotrophic lateral sclerosis-related superoxide dismutase 1 (SOD1) mutants trigger a pathological UPR, leading to motor neuron dysfunction (Nishitoh et al, 2008). The contributions of Derlin-1 to normal brain development have not been established
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