Improved proteostasis in the secretory pathway rescues Alzheimer’s disease in the mouse

Abstract

The aberrant accumulation of toxic protein aggregates is a key feature of many neurodegenerative diseases, including Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease. As such, improving normal proteostatic mechanisms is an active target for biomedical research. Although they share common pathological features, protein aggregates form in different subcellular locations. Nε-lysine acetylation in the lumen of the endoplasmic reticulum has recently emerged as a new mechanism to regulate the induction of autophagy. The endoplasmic reticulum acetylation machinery includes AT-1/SLC33A1, a membrane transporter that translocates acetyl-CoA from the cytosol into the endoplasmic reticulum lumen, and ATase1 and ATase2, two acetyltransferases that acetylate endoplasmic reticulum cargo proteins. Here, we used a mutant form of α-synuclein to show that inhibition of the endoplasmic reticulum acetylation machinery specifically improves autophagy-mediated disposal of toxic protein aggregates that form within the secretory pathway, but not those that form in the cytosol. Consequently, haploinsufficiency of AT-1/SLC33A1 in the mouse rescued Alzheimer's disease, but not Huntington's disease or amyotrophic lateral sclerosis. In fact, intracellular toxic protein aggregates in Alzheimer's disease form within the secretory pathway while in Huntington's disease and amyotrophic lateral sclerosis they form in different cellular compartments. Furthermore, biochemical inhibition of ATase1 and ATase2 was also able to rescue the Alzheimer's disease phenotype in a mouse model of the disease. Specifically, we observed reduced levels of soluble amyloid-β aggregates, reduced amyloid-β pathology, reduced phosphorylation of tau, improved synaptic plasticity, and increased lifespan of the animals. In conclusion, our results indicate that Nε-lysine acetylation in the endoplasmic reticulum lumen regulates normal proteostasis of the secretory pathway; they also support therapies targeting endoplasmic reticulum acetyltransferases, ATase1 and ATase2, for a subset of chronic degenerative diseases.

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

“…We previously reported that the influx of acetyl‐CoA from the cytosol to the ER lumen by AT‐1 regulates the induction of ER‐autophagy and the disposal of protein aggregates within the secretory pathway (Jonas et al, 2010; Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014 ). Therefore, it is possible that a defect in ER‐autophagy (also referred to as reticulophagy) is at the basis of the progeria‐like phenotype of AT‐1 sTg mice.…”

“…To test the above hypothesis, we first analyzed the acetylation profile of the autophagy protein Atg9a, which is essential for the induction of autophagy downstream of the ER acetylation machinery (Pehar et al, 2012; Peng & Puglielli, 2016; Peng et al, 2016, 2014 ). In fact, Atg9a undergoes acetylation on two lysine residues, K359 and K363, which face the lumen of the ER (Pehar et al, 2012).…”

“…To assess whether the increased acetylation of Atg9a was accompanied by reduced disposal of misfolded/aggregated ER cargo proteins, we took advantage of the pro‐aggregating properties of the A53 T mutant form of α‐synuclein (A53 T syn; Polymeropoulos et al, 1997). Specifically, we used A53 T syn with a signal peptide (SP) at the N‐terminus to direct translation on the ER and insertion into the secretory pathway (Peng et al, 2016). The results show that when expressed in MEF, the levels of aggregated/SDS soluble SP‐A53 T syn were higher in AT‐1 sTg vs. WT animals (Supporting Information Figure S3a,b).…”

“…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 ).…”