ReviewAutophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy
Introduction
Autophagy (which means “self-eating”) is a lysosome degradation pathway by which cells capture intracellular proteins, lipids and organelles, and deliver them to the lysosomal compartment where they are degraded (Levine and Klionsky, 2004, Levine and Kroemer, 2008). It plays an important homeostatic role in cells and keeps the metabolic balance between synthesis, degradation, and subsequent turnover of cytoplasmic materials in stressful environment. Autophagy is classified into 3 types: macroautophagy, chaperone-mediated autophagy (CMA), and macroautophagy (Cuervo, 2004). Increasing studies have observed that autophagic vacuoles (AVs), the general term for autophagy-related vesicular structures, are abundant in neurons in an increasing number of neurodegenerative disorders that are manifested by the presence of pathogenic proteins. Moreover, in the context of neurodegenerative disorders, the view that induction of autophagy is a neuroprotective response and that aberrant autophagy promotes neuronal cell death in most of these disorders has been widely accepted. Given these observations, autophagy as a potential therapeutic target in aging and neurodegenerative diseases is currently receiving more and more attention. In this review, we will focus on aging and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and lysosomal storage disorders (LSDs), after briefly reviewing the mechanisms and function of autophagy. Furthermore, we also discuss how current knowledge about autophagy could be harnessed to open exciting new therapeutic perspectives for aging and neurodegenerative disorders.
Section snippets
The machinery of autophagy
The proteins that are encoded by autophagy-related-genes (ATGs), ATG1-ATG35, organize into functional complexes that mediate the following steps in the autophagic processes: initiation, elongation, maturation and fusion, and degradation (Table 1) (Fig. 1). The process begins with the formation of a pre-autophagosomal structure or phagophore, which is probably derived from the lipid bilayer of the plasma membrane, including endoplasmic reticulum, golgi apparatus, plasma membrane, or mitochondria
mTOR-dependent signaling pathways
The mTOR is a primordial inhibitory signal, which participates in the initial process of signal transduction, acting the upstream of ATG proteins. mTORC1 and mTORC2, 2 functionally distinct multi-protein complexes, are the main subunit of mTOR. However, only the rapamycin-sensitive mTORC1 directly controls cellular homeostasis via the inhibition of autophagy (Hosokawa et al., 2009) (Fig. 2). When growth factors like insulin-like growth factor bind to insulin-like growth factor receptors
Autophagy in maintaining neuronal homeostasis
The role of autophagy in maintaining neuronal homeostasis is particularly vital for postmitotic neurons, where the level of altered proteins and damaged organelles cannot be diluted by means of cell division. Moreover, the neurons possess the specialized cellular structures for intercellular communication. Thus, postmitotic neurons with specialized cellular structures have distinct mechanism of autophagic regulation compared with that of nonneuronal cells. In cultured primary neurons, blockage
A common series of events in neurodegeneration
Neurodegenerative disorders display the dynamic variety in the diverse stages failures, regional susceptibility, and pathologic mechanisms. Nevertheless, almost all neurodegenerative diseases are age-dependent hereditary or sporadic disorders that are manifested by progressive loss of neural function. One common feature in their pathogenesis is the way in which neurons dispose the presence of pathogenic proteins. Many pathogenic proteins can be degraded through either the ubiquitin-proteasome
Autophagy in aging
Almost all aging organisms share a gradual decrease in the activity of both the ubiquitinproteasome system and autophagy, which is believed to constitute an aging process. Numerous evidences now indicate that autophagy declines with age and this progressive reduction might have a causative role in the functional deterioration of biological systems during aging. A recent commendable mouse model, senescence accelerated mouse prone 8 (SAMP8), which is a non-genetically modified stain of mice with
Autophagy in neurodegenerative diseases
Autophagic dysfunctions are referred as a secondary pathologic mechanism for various neurodegenerative diseases, such as AD, PD, HD, and ALS (Nixon, 2006). Moreover, each neurodegenerative disease is related to defects in different steps of the autophagic pathway and in different types of autophagy (Fig. 3).
Pharmacologic manipulation of autophagy
As many diseases are caused by abnormal proteins, the therapeutic strategy that can enhance the elimination of these toxic proteins in the cytoplasm might be viable. Indeed, it has been proved that promoting the clearance of aggregate-prone proteins via pharmacologic induction of autophagy can achieve the goal of protecting cells from the toxicity of these proteins (Fig. 5). Another benefit of autophagy up-regulation is that it may protect cells against apoptotic insults and necrotic cell death
Concluding remarks and future perspectives
Increasing evidence has firmly certified the neuronal autophagy is an essential anchor for delaying aging and many neurodegenerative diseases process, such as AD, PD, HD, and ALS. The use we make of the beneficial factors of autophagy and the control we have of the detrimental factors of autophagy depends on our knowledge of their role in these disorders. The use we make of the beneficial factors of autophagy and the control we have of the detrimental factors of autophagy depend on our
Disclosure statement
The authors declare no conflicts of interest.
Acknowledgements
This work was supported in part by grants from the National Natural Science Foundation of China (81000544, 81171209, 81371406), and the Shandong Provincial Natural Science Foundation, China (ZR2010HQ004, ZR2011HZ001).
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