References for this Review were identified by searches of peer-review journals on PubMed using the search terms “autophagy”, “neurodegeneration”, “disease”, “lysosomes”, and “protein degradation”. When possible, original manuscripts were used as references in support of each statement. However, because of the limitations in the number of references allowed for this type of contribution, some statements are supported by review papers. In that case, the most recent review papers by leaders
ReviewAutophagy and neurodegeneration: when the cleaning crew goes on strike
Introduction
With regards to cell biology, neurodegenerative disorders are catalogued as a broader group of pathologies generically known as protein conformational disorders. All of these disorders originate when a particular protein (or group of proteins) “misbehaves” and accumulates inside cells in the form of toxic structures, which induce cellular damage and eventually cell death. Misbehaviour of a protein signifies any kind of modification that alters its proper conformation—the one that makes it stable and functional. Conformational alterations may be the result of inadequate folding of the protein when it is synthesised, unfolding at some point during its life cycle, abnormal cleavage, or additions, deletions, or modifications in its amino-acid sequence. From the moment a protein is synthesised inside a cell until the time it is eliminated, cellular systems continuously check on the quality of the protein and take care of its repair or removal from the cell if there is any abnormality. In all protein conformational disorders there is an imbalance between the capability or activity of these quality control systems and the amount of altered proteins in the cells, which progressively leads to the intracellular accumulation of abnormal proteins. The rapid advance during the past decade in understanding the quality control systems of cellular proteins has allowed the identification of unambiguous associations between malfunctioning of these systems and some severe human pathologies, including major neurodegenerative disorders. Furthermore, interventions that aim to improve the quality control systems inside cells are currently being explored as possible therapeutic approaches in these disorders.
In this Review, we summarise the role of autophagy—one of the intracellular surveillance mechanisms involved in the pathogenesis of neurodegenerative disorders—and we discuss current attempts to modulate the activity of this system for therapeutic purposes.
Section snippets
Autophagy: the lysosomal system
It is now more than 60 years since the identification and characterisation of the lysosome—an intracellular organelle completely devoted to the degradation or recycling of intracellular and extracellular components.1 The participation of the lysosomal system in the regulation of cell-surface molecules and receptors in the plasma membrane, as well as its role in the defence against extracellular aggressors, has been extensively characterised. This lysosomal degradation of exogenous products is
Autophagy and the quality control system
The ability of autophagy to completely remove intracellular contents makes the lysosomal system an essential part of the quality control systems inside cells, along with the ubiquitin-proteasome system (figure 1)—the other major proteolytic complex—and the chaperones, which are responsible for identification of altered components.
Alterations in intracellular proteins can be due to intracellular or extracellular aggressors (oxidative stress, ultraviolet radiation, toxic compounds). In other
A common series of events in neurodegeneration
Despite the individual intricacies of each neurodegenerative disorder, there are some common features, mostly those associated with the way in which neurons handle the presence of the altered proteins. Recent studies support the existence of a common course of events shared by all of these disorders (figure 3).17, 37 Altered proteins that still maintain their solubility are normally targeted for degradation through either the ubiquitin-proteasome system or CMA. Degradation through these systems
Autophagy in neurodegenerative disorders
The implications of autophagic failure in neurodegeneration partly originated from studies on particular neurodegenerative disorders. It is only recently that this abnormal protein handling has been recognised as a common theme in all neurodegenerative disorders. We describe here how studies in three major neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, and polyglutamine disorders, have contributed to our understanding of the role of autophagy in neurodegeneration, and
Effect of ageing on autophagy
Although some of the altered proteins are present since birth, for some patients with neurodegenerative disorders pathology appears only late in life; for instance, in many neurodegenerative disorders symptoms only appear after age 60 years. A progressive deterioration of the intracellular quality control systems with age has been proposed as the main reason for the late onset of these neurodegenerative pathologies.59, 91
A decrease in the activity of both the ubiquitin-proteasome system and
Manipulating autophagic pathways
Since the initial observations that associated problems within the protein-clearance systems with neurodegenerative disorders, there has been a growing interest in identifying the reasons for the failure of these systems so that normal activity can be restored. We still do not know why some mutant proteins block proteasome function, or why some others cannot translocate across the lysosomal membrane via CMA like their normal counterparts do. However, manipulation of macroautophagy, in an
Conclusion
There is convincing evidence to support the idea that deficiencies in cellular quality control systems are the basis of common neurodegenerative disorders. Part of the defect is due to a direct toxic effect of the altered proteins on clearance systems. However, aggravating conditions, such as oxidative stress or ageing, known to affect the functioning of these systems, are likely to precipitate their failure. Future studies should focus on the mechanisms by which altered proteins affect
Search strategy and selection criteria
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