Ubiquitin, Autophagy and Neurodegenerative Diseases

Abstract

Ubiquitin signals play various roles in proteolytic and non-proteolytic functions. Ubiquitin signals are recognized as targets of the ubiquitin-proteasome system and the autophagy-lysosome pathway. In autophagy, ubiquitin signals are required for selective incorporation of cargoes, such as proteins, organelles, and microbial invaders, into autophagosomes. Autophagy receptors possessing an LC3-binding domain and a ubiquitin binding domain are involved in this process. Autophagy activity can decline as a result of genetic variation, aging, or lifestyle, resulting in the onset of various neurodegenerative diseases. This review summarizes the selective autophagy of neurodegenerative disease-associated protein aggregates via autophagy receptors and discusses its therapeutic application for neurodegenerative diseases.

Keywords: autophagy; autophagy–lysosome pathway; neurodegenerative diseases; ubiquitin; ubiquitin–proteasome system.

Figure 1

Degradation of ubiquitinated cargoes. Harmful proteins and mitochondria can be modified by various ubiquitin additions, such as mono-ubiquitin and Lys-11-, Lys-48-, and Lys-63-poly-ubiquitin chains. The proteasome preferentially degrades mono-ubiquitinated proteins and Lys11- and Lys-48-linked proteins, whereas autophagy preferentially eliminates Lys-48-, and Lys-63- decorated protein aggregates and mitochondria.

Figure 2

Ubiquitination of neurodegenerative disease-associated proteins. Neurodegenerative disease-associated proteins, such as Tau, APP (β-amyloid precursor protein), α-synuclein, TDP43, SOD1, and Huntingtin are ubiquitinated at individual target sites. Specific ubiquitin ligases involved in this ubiquitination and the pattern of ubiquitin chains can be identified by various biochemical studies.

Figure 3

Autophagy receptors and selective autophagy of ubiquitinated cargoes. (A) Autophagy receptors play an important role in selective autophagy. Appropriate autophagy receptors bind to various ubiquitinated cargoes (Lys-48-, Lys-63-, linear-poly-ubiquitin chain, and mono-ubiquitin) through their ubiquitin binding domain. Many autophagy receptors are regulated by various kinases, and then autophagy receptor-cargo complexes interact with the autophagosome protein, LC3. (B) Structure of major autophagy receptors. Autophagy receptors consist of an LIR domain and a ubiquitin binding domain. Ubiquitin binding domains (UBA, UBAN, and ZnF) are classified based on motif sequences. Biochemical studies show preferences of autophagy receptors for ubiquitin types.