Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation

Abstract

Increased expression of the ER membrane acetyl-CoA transporter AT-1 can cause an autism-like phenotype in mice.

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

“…Previous data in MEF from AT‐1 S113R/+ mice and H4 cells overexpressing AT‐1 indicate that changes in autophagy induction downstream of AT‐1 are also paralleled by changes in efficiency of the secretory pathway; specifically, reduced AT‐1 activity leads to reduced trafficking of newly synthesized glycoproteins along the secretory pathway while increased AT‐1 activity leads to the opposite effect (Hullinger et al, 2016). To test whether this was indeed the case in AT‐1 sTg mice, we used azide‐modified mannosamine (ManNAz) to label sialic acid‐containing newly synthesized glycoproteins that have successfully trafficked from the ER to the trans ‐Golgi (Hullinger et al, 2016).…”

“…Nε‐lysine acetylation in the lumen of the endoplasmic reticulum (ER) has emerged as a novel mechanism for the regulation of protein homeostasis (also referred to as proteostasis) within the organelle (Ding, Dellisanti, Ko, Czajkowski, & Puglielli, 2014; Hullinger et al, 2016; Jonas, Pehar, & Puglielli, 2010; Pehar, Jonas, Hare, & Puglielli, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014). Acetylation of ER cargo proteins is ensured by three essential elements: AT‐1, ATase1, and ATase2.…”

“…ATase1 (also referred to as NAT8B) and ATase2 (also referred to as NAT8) are type II ER membrane proteins that carry out the reaction of Nε‐lysine acetylation within the ER lumen (Ding et al, 2014; Ko & Puglielli, 2009). Ex vivo and in vivo data suggest that the ER acetylation machinery is a component of ER quality control and regulates two essential functions of the organelle: (a) selection and transport of cargo proteins along the secretory pathway; and (b) disposal of protein aggregates that form within the ER and secretory pathway (Ding et al, 2014; Hullinger et al, 2016; Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014). The former requires the ATases to associate with the oligosaccharyltransferase complex (OST) and acetylate correctly folded polypeptides (Ding et al, 2014; Peng & Puglielli, 2016) while the latter requires acetylation/deacetylation of the autophagy protein Atg9a (Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014 ).…”

“…Knock‐in mice that lack AT‐1 activity (AT‐1 S113R/S113R ) die during embryogenesis, while mice with haploinsufficiency of AT‐1 (AT‐1 S113R/+ ) develop neurodegeneration with spasticity and propensity to infections and cancer (Peng et al, 2014). Transgenic mice that overexpress AT‐1 in forebrain neurons (AT‐1 Tg) display an ASD‐like phenotype without dysmorphism (Hullinger et al, 2016). Mechanistically, the phenotype of AT‐1 S113R/+ mice is linked to aberrant activation of autophagy (Peng et al, 2014) while the phenotype of AT‐1 Tg is linked to increased efficiency of the secretory pathway (Hullinger et al, 2016).…”

“…Transgenic mice that overexpress AT‐1 in forebrain neurons (AT‐1 Tg) display an ASD‐like phenotype without dysmorphism (Hullinger et al, 2016). Mechanistically, the phenotype of AT‐1 S113R/+ mice is linked to aberrant activation of autophagy (Peng et al, 2014) while the phenotype of AT‐1 Tg is linked to increased efficiency of the secretory pathway (Hullinger et al, 2016). When taken together, the convergence of human‐ and mouse‐based studies clearly indicates that the ER acetylation machinery plays fundamental biological functions.…”