Autophagy gone awry in neurodegenerative diseases

Abstract

Autophagy is essential for neuronal homeostasis, and its dysfunction has been directly linked to a growing number of neurodegenerative disorders. The reasons behind autophagic failure in degenerating neurons can be very diverse because of the different steps required for autophagy and the characterization of the molecular players involved in each of them. Understanding the step(s) affected in the autophagic process in each disorder could explain differences in the course of these pathologies and will be essential to developing targeted therapeutic approaches for each disease based on modulation of autophagy. Here we present examples of different types of autophagic dysfunction described in common neurodegenerative disorders and discuss the prospect of exploring some of the recently identified autophagic variants and the interactions among autophagic and non-autophagic proteolytic systems as possible future therapeutic targets.

Figure 1. Possible steps of macroautophagy altered in neurodegeneration

The possible defects that could be behind macroautophagy malfunctioning in different neurodegenerative disorders are depicted: 1. Reduced autophagy induction; 2. Enhanced autophagy repression; 3. Altered cargo recognition; 4. Inefficient autophagosome/lysosome fusion, and 5. Inefficient degradation of the autophagic cargo in lysosomes. Examples of neurodegenerative diseases for which alterations in each autophagic step have been described are shown. Atg: autophagy-related proteins; Vps: vesicular protein secretion protein; HDAC: histone deacetylase; AD: Alzheimer’s disease; HD: Huntington’s disease; PD: Parkinson’s diease; LSD: lysosomal storage disorders; SMA: spinal muscular atrophy.

Figure 2. Cross-talk among macroautophagy and different cellular proteolytic systems

The consequences of macroautophagic blockage on the activity of other autophagic pathways, endocytosis and on the ubiquitin proteasome system (UPS) and the consequences of changes in these pathways on macroautophagy are depicted. Examples of neurodegenerative disorders for which this crosstalk has been shown to be relevant are indicated in the red boxes and are discussed in more detail in the text. MVB: multivesicular bodies; CMA: chaperone-mediated autophagy; UPS: ubiquitin proteasome system; AD: Alzheimer’s disease; HD: Huntington’s disease; PD: Parkinson’s diease; FTP:frontotemporal dementia; ALS: amyotrophic lateral sclerosis; SMA: spinal muscular atrophy.

Figure 3. Variations of the macroautophagic process

Types of macroautophagy depending on the stimuli that mediates its activation (Top) or on the molecular mechanisms involved in autophagy activation/execution (Bottom). As new understanding of these different autophagy variants is gained, it is possible that activation of one autophagic variant could be utilized to compensate for defects in other autophagy variant.