Association Between Autophagy and Neurodegenerative Diseases

Abstract

Autophagy is a phylogenetically conserved mechanism that controls the degradation of subcellular constituents, including misfolded proteins, and damaged organelles. The progression of many neurodegenerative diseases is thought to be driven by the aggregation of misfolded proteins; therefore, autophagic activity is thought to affect disease severity to some extent. In some neurodegenerative diseases, the suppression of autophagic activity accelerates disease progression. Given that the induction of autophagy can potentially mitigate disease severity, various autophagy-inducing compounds have been developed and their efficacy has been evaluated in several rodent models of neurodegenerative diseases.

Keywords: Alzheimer disease; Parkinson disease; amyotrophic lateral sclerosis; autophagy; neurodegenerative disease; polyglutamine disease; tauopathy.

Figure 1

Hypothetical model of autophagy. There are at least two modes of macroautophagy, i.e., conventional and alternative autophagy. Conventional autophagy requires Atg5 and Atg7, is associated with LC3 modification, and is thought to originate from the ER membrane. After Ulk1 stimulation, Atg5-12 complexes (red circles) attach to isolation membranes, and then LC3-PE puncta (green circles) are incorporated into autophagosomal membranes. In contrast, alternative autophagy occurs independently of Atg5 and Atg7, as well as LC3 modification. The generation of autophagic vacuoles in alternative autophagy is mediated by the fusion of isolation membranes with vesicles derived from the trans-Golgi as well as late endosomes, in a Rab9-dependent manner. After Ulk1 stimulation, Rab9 puncta (purple circles) attach to autophagic membranes.

Figure 2

Relationship between neurodegenerative diseases and autophagy. A common pathology shared by several neurodegenerative diseases is the accumulation of misfolded proteins and inclusion bodies. Autophagy may be useful for degrading both misfolded proteins and inclusion bodies.