Trends in Neurosciences
ReviewAutophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications
Introduction
Autophagy or self-eating is a lysosome-mediated degradation process for non-essential or damaged cellular constituents. It plays an important homeostatic role in cells and preserves the balance between synthesis, degradation and subsequent recycling of cellular components [1]. During autophagy, cytoplasmic constituents (including misfolded or aggregated proteins), damaged organelles [such as mitochondria, endoplasmic reticulum (ER) and peroxisomes], and intracellular pathogens are sequestered into double-membrane autophagosomes and their contents are then degraded by lysosomal hydrolases. This machinery has been implicated in multiple physiological processes, including protein and organelle turnover, stress response, cellular differentiation and programmed cell death, in addition to various pathological settings [2]. Whereas basal levels of autophagy ensure the physiological turnover of old and damaged organelles as a garbage removal process, it is thought that significant accumulation of autophagosomes is either an alternative pathway of cell death or an ultimate cellular survival attempt in response to stress [3].
It has recently been observed that autophagosomes are abundant in neurons in an increasing number of neurodegenerative disorders. Such observations have provoked controversial viewpoints about whether these structures foster neuronal cell death or render neuroprotection. It is often debated whether autophagosome accumulation in neurons leads to an increase in autophagic activity or rather is a consequence of impaired autophagic degradation leading to a buildup of autophagosomes. Whether autophagy induction in neurons leads to cell death (traditionally mediated via conserved canonical pathways such as apoptosis and necrosis [4]) or simply occurs as a process alongside these other pathways is a controversial issue. Thus, it is crucial to address these opposing views in defining its fundamental role in neuronal physiology [5].
It is becoming increasingly evident that autophagy can contribute differently to cell death induction according to the type and degree of environmental changes or stress stimuli. Cell response might gradually shift from elimination of damaged proteins and organelles via autophagy, which leads to its recovery, to the induction of apoptotic pathways determining cellular demise. However, in the context of neurodegenerative disorders, an emerging consensus is the view that induction of autophagy is a neuroprotective response and that inadequate or defective autophagy, rather than excessive autophagy, promotes neuronal cell death in most of these disorders [6]. In this review, we provide an overview of current understanding of the putative role of autophagy mechanisms in common neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Furthermore, we discuss how current knowledge about this degradation machinery could be harnessed to design potential therapeutic approaches.
Section snippets
The autophagy process
Autophagy was first described by Christian De Duve in 1963 as a cellular process in which a double-membrane vesicle, the autophagosome, delivers cytoplasmic constituents to lysosomes for degradation and recycling [7]. Our understanding of the genetic basis of this physiological process remained ambiguous until a decade ago, when over 30 autophagy-related genes (ATG) and their roles in the regulation and execution of autophagy at the molecular level were identified [8]. This machinery involves
Regulation of autophagy in common neurodegenerative disorders
Cytoplasmic, nuclear and extracellular inclusions composed of aggregated and ubiquitinated proteins are key pathological hallmarks of numerous neurodegenerative diseases. It is believed that protein aggregation contributes to organelle damage, synaptic dysfunction and neuronal degeneration, so clearance pathways for intracellular protein aggregates have been suggested as a potential therapeutic approach for such disorders. It is now apparent that aggregate-prone proteins and damaged organelles
Concluding remarks
Protein aggregation and organellar dysfunction are characteristic features of many late-onset neurodegenerative diseases. Subsequent accumulation of damaged proteins and organelles leads to a mass of toxic debris within afflicted neurons that results in neuronal dysfunction and can ultimately cause cell death. Accumulating evidence suggests that acceleration of the removal of toxic accumulations of damaged membranes, organelles and proteins might be a tractable therapeutic strategy for
Acknowledgements
This work was supported by National Institutes of Health grants NS060885, NS062165 (B.T.) and ES017295 (M.F.B.), and grants from the Michael J. Fox Foundation for Parkinson's disease (B.T and M.F.B) and the Department of Defense (M.F.B.).
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