ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function

Abstract

Derlin-1 and Derlin-2 are essential for postnatal brain development and function Chemical chaperon does not ameliorate the phenotype of Derlindeficient neuron Derlin regulates SREBP-2 activation and promotes brain cholesterol biosynthesis Derlin-mediated cholesterol biosynthesis is essential for neurite outgrowth

Regulation of Derlin-1-mediated degradation of NADPH oxidase partner p22 by thiol modification

“…Derlin-1 is implicated in ERAD and interacts with misfolded transmembrane proteins during their transfer from the ER to the cytosolic proteasome [ [27] , [28] , [29] , [30] ]. To determine whether p22 phox mutant proteins bind to Derlin-1, Derlin-1–FLAG proteins were immunoprecipitated from the cell lysates of CHO–K1 cells expressing exogenous p22 phox –Myc and Derlin-1–FLAG proteins.…”

“…They are then degraded by the ubiquitin–proteasome system [ 43 ]. Derlin-1 is part of a channel for retro-translocation and is essential for the degradation of misfolded membrane proteins [ [27] , [28] , [29] , [30] ], such as cystic fibrosis transmembrane conductance regulator (CFTR)-ΔF508 mutant protein [ 44 , 45 ]. Herein, we demonstrated that in the ER, the substitution of Leu-51, Leu-52, Glu-53, and Pro-55 facilitates the interaction of p22 phox with Derlin-1 ( Fig.…”

“…In the present study, we characterized missense mutations in p22 phox (L51Q, L52P, E53V, and P55R) and demonstrated that these amino acid substitutions promote the degradation of p22 phox protein in the ER. Interestingly, all of the mutant proteins strongly promoted the binding of p22 phox to Derlin-1, a key component of the ERAD system [ [27] , [28] , [29] , [30] ]. These findings suggest that these amino acids (Leu-51, Leu-52, Glu-53, and Pro-55) are responsible for the stability of p22 phox protein in the ER.…”

miRNA Expression Is Increased in Serum from Patients with Semantic Variant Primary Progressive Aphasia

“…Interestingly, among the 39 common mRNAs targets for miR-133a-3p and miR-106b-5p, there is a DERL2 gene, encoding for Derlin-2 protein, one of the endoplasmic reticulum (ER) membrane proteins and part of the ERAD degradation complex which eliminates unfolded proteins [ 38 ]. Recent findings by Sugiyama et al demonstrated that Derlin-2-deficient mice have widespread postnatal brain atrophy in the cerebellum and striatum as well as reduced neurite outgrowth and motor function deficits [ 39 ]. We can hypothesize that a generalized downregulation of miRNAs observed in lvPPA could lead to a translation upregulation and an alteration of target gene expression [ 40 ] and vice-versa in svPPA.…”

GPHR‐mediated acidification of the Golgi lumen is essential for cholesterol biosynthesis in the brain

“…Loss of SCAP protein in the brain affects brain morphology and neuronal activity, indicating that proper cholesterol content is important for brain homeostasis [48]. In addition, it has been reported that mice with central nervous system‐specific ablation of Derl‐1 , which encodes Derlin‐1 that is essential for ER quality control, exhibited brain atrophy and motor dysfunction due to suppression of SREBP2‐mediated cholesterol biosynthesis [49]. These reports are consistent with the phenotypes observed in the GPHR f/f ;Nes mouse brain.…”