Kinetics of Protein Aggregates Disposal by Aggrephagy

Abstract

Macroautophagy has generated considerable interest because of its ability to recognize and target protein inclusions found prevalent in neurodegenerative diseases to lysosomes for elimination. Pharmacological upregulation of macroautophagy to remove disease-linked aggresomes has been reported to slow down disease progression and to improve survivability in many neurodegenerative models. Despite its bulk removal mechanism, we now know that there are selective forms of autophagy. Defect in selective autophagy represents a prominent cause of autophagic failures in many disorders. Aggrephagy refers to the selective degradation of protein aggregates by macroautophagy. In this chapter, we will review the mechanisms and factors that govern the selectivity of protein aggregates for disposal by macroautophagy. This understanding is paramount for us to develop therapeutic approaches to enhance specific cargo targeting in addition to general upregulation of macroautophagy for mitigating disease progression. In addition, we will provide an overview of the different experimental models of protein inclusions, as well as the microscopy and biochemical techniques used to quantitatively analyze the abundance of protein inclusions and the kinetics of their turnovers by macroautophagy.

Keywords: Aggregates; Aggrephagy; Aggresome; Autophagy receptors; Macroautophagy; Neurodegenerative diseases; Posttranslational modifications; Proteotoxic stress; Ubiquitinated protein inclusions.