The elimination of accumulated and aggregated proteins: a role for aggrephagy in neurodegeneration

Abstract

The presence of ubiquitinated protein inclusions is a hallmark of most adult onset neurodegenerative disorders. Although the toxicity of these structures remains controversial, their prolonged presence in neurons is indicative of some failure in fundamental cellular processes. It therefore may be possible that driving the elimination of inclusions can help re-establish normal cellular function. There is growing evidence that macroautophagy has two roles; first, as a non-selective degradative response to cellular stress such as starvation, and the other as a highly selective quality control mechanism whose basal levels are important to maintain cellular health. One particular form of macroautophagy, aggrephagy, may have particular relevance in neurodegeneration, as it is responsible for the selective elimination of accumulated and aggregated ubiquitinated proteins. In this review, we will discuss the molecular mechanisms and role of protein aggregation in neurodegeneration, as well as the molecular mechanism of aggrephagy and how it may impact disease. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."

Figure 1. Schematic summary of macroautophagy

Although the origin of the autophagosomal membrane is still a matter of discussion, the early steps of autophagosome formation (nucleation and expansion) are known to require the following proteins: i) the Atg1/unc-51-like kinase (ULK) complex; ii) the Vps34/class III phosphatidylinositol 3-kinase (PI3K) complex I; iii) the transmembrane protein Atg9 and its cycling from the TGN and iv) the two ubiquitin-like proteins Atg12 and LC3 (the mammalian homologue of Atg8) and their conjugation systems (see text for details). Autophagosome maturation involves fusion with different endocytic compartments (early endosomes, multivesicular bodies and late endosomes) to form amphisomes containing both autophagosomal and endosomal content or autophagosomes might fuse directly with lysosomes. Finally the sequestered cytoplasmic material becomes degraded and the resulting macromolecules recycled back to the cytosol to be reused by the cell.

Figure 2. Schematic comparison between models of Cvt and aggrephagy

A. Cvt. The precursor Ape1 is oligomerized into a 12-mer then further aggregated into the Ape1 complex. The autophagy receptor protein Atg19 then binds to the ApeI complex and attracts Atg11 which brings the complex to the phagophore. Atg11 is displaced by PE-bound Atg8 and Cvt vesicle forms around the complex. The PI3P-binding proteins Atg20, Atg21 and Atg24 are also involved in the Cvt pathway. B. Aggrephagy. The aggregate-prone protein becomes ubiquitinated and oligomerize. p62 binds to the ubiquitinated proteins and drives the formation of aggregates. Aggresome-like larger aggregates may continue to form but are not shown. The inclusion attracts Alfy, which is important for recruitment of Atg5-Atg12 to the inclusion. The presence of Alfy also stabilizes the interaction of LC3 with the inclusion. Alfy binds to PI3P in the autophagic membrane and may facilitate binding of Atg5-Atg12 to the membrane associated Atg16, creating the Atg5-Atg12-Atg16 complex, which might work as an E3-like ligase to permit LC3 conjugation to PE in the membrane, and formation of the autophagomes around the inclusion.