Targeting endoplasmic reticulum acetylation to restore proteostasis in Alzheimer's disease.

Abstract

This scientific commentary refers to ‘Improved proteostasis in the secretory pathway rescues Alzheimer’s disease in the mouse’, by Peng et al. (doi:10.1093/brain/awv385). Maintaining the health of the proteome is essential for sustaining biological functions. The buffering capacity of the proteostasis network is reduced during ageing, which represents the major risk factor for most common neurodegenerative diseases. In fact, independent of the aetiology of the disease, the misfolding and aggregation of specific proteins is a hallmark of many neurodegenerative conditions, which are now classified as protein misfolding disorders. Quality control pathways recognize aberrant proteins and promote their clearance by different routes, in particular the ubiquitin–proteasome system and macroautophagy (hereafter referred to as autophagy) (Vilchez et al. , 2014). The endoplasmic reticulum (ER) is the subcellular compartment responsible for protein synthesis and folding of nearly one-third of the total proteome. Several homeostatic mechanisms control the fidelity and efficiency of the protein folding process at the ER, including the unfolded protein response (UPR), the ER-associated degradation (ERAD) pathway, and the calnexin and calreticulin cycle, among others. Recently, new post-translational modifications of ER clients were discovered in the form of acetylation of lysines, an event that serves as quality control of protein-folding intermediaries. In this issue of Brain , Peng and co-workers report that inhibiting the acetylation of nascent proteins can control ER proteostasis through a novel mechanism that modulates autophagy, providing neuroprotection in models of Alzheimer’s disease (Peng et al. , 2016). Maintaining the efficiency of the protein-folding process in the ER represents a constant challenge for the cell, where proteins with several hydrophobic transmembrane domains are folded with low rates of success. Furthermore, most secretory proteins undergo sequential post-translational modifications including glycosylation, disulfide bond formation, glycophosphatidylinositol (GPI) tagging, and proteolytic processing, in addition to the assembly of multimeric …