Autophagy as a Stress-Response and Quality-Control Mechanism: Implications for Cell Injury and Human Disease

Department of Pathology, Helen Diller Family Comprehensive Cancer Center, and Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143
Annual Review of Pathology Mechanisms of Disease (Impact Factor: 18.75). 10/2012; 8(1). DOI: 10.1146/annurev-pathol-020712-163918
Source: PubMed

ABSTRACT Autophagy, a vital catabolic process that degrades cytoplasmic components within the lysosome, is an essential cytoprotective response to pathologic stresses that occur during diseases such as cancer, ischemia, and infection. In addition to its role as a stress-response pathway, autophagy plays an essential quality-control function in the cell by promoting basal turnover of long-lived proteins and organelles, as well as by selectively degrading damaged cellular components. This homeostatic function protects against a wide variety of diseases, including neurodegeneration, myopathy, liver disease, and diabetes. This review discusses our current understanding of these two principal functions of autophagy and describes in detail how alterations in autophagy promote human disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 8 is January 24, 2013. Please see for revised estimates.

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    • "Autophagy is a catabolic process aimed at degrading damaged organelles, proteins and cellular debris by engulfing them into a double membrane vesicle called the autophagosome and eliminating them by posterior fusion with the lysosome (Flores-Bellver et al., 2014). Overactive autophagy may be cytotoxic (Murrow and Debnath, 2013). Autophagy is characterized by the formation of the autophagosome containing lipidated LC3. "
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    Ageing Research Reviews 09/2015; DOI:10.1016/j.arr.2015.09.002 · 4.94 Impact Factor
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    • "Several studies have shown that autophagy dysfunction contributes to the pathogenesis of several neurological diseases, resulting in an abnormal accumulation of proteins (Murrow and Debnath, 2013), such as in chronic tauopathies (e.g., AD) and acute tauopathies (e.g., CI; Nixon and Yang, 2011; Dohi et al., 2012). However, the mechanisms underlying these pathologies are not clearly understood. "
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    ABSTRACT: Alzheimer’s disease (AD) and cerebral ischemia (CI) are neuropathologies that are characterized by aggregates of tau protein, a hallmark of cognitive disorder and dementia. Protein accumulation can be induced by autophagic failure. Autophagy is a metabolic pathway involved in the homeostatic recycling of cellular components. However, the role of autophagy in those tauopathies remains unclear. In this study, we performed a comparative analysis to identify autophagy related markers in tauopathy generated by AD and CI during short-term, intermediate, and long-term progression using the 3xTg-AD mouse model (aged 6,12, and 18 months) and the global CI 2-VO (2- Vessel Occlusion) rat model (1,15, and 30 days post-ischemia). Our findings confirmed neuronal loss and hyperphosphorylated tau aggregation in the somatosensory cortex (SS-Cx) of the 3xTg-AD mice in the late stage (aged 18 months), which was supported by a failure in autophagy. These results were in contrast to those obtained in the SS- Cx of the CI rats, in which we detected neuronal loss and tauopathy at 1 and 15 days post-ischemia, and this phenomenon was reversed at 30 days. We proposed that this phenomenon was associated with autophagy induction in the late stage, since the data showed a decrease in p-mTOR activity, an association of Beclin-1 and Vps34, a progressive reduction in PHF-1, an increase in LC3B puncta and autophago-lysosomes formation were observed. Furthermore, the survival pathways remained unaffected. Together, our comparative study suggest that autophagy could ameliorates tauopathy in CI but not in AD, suggesting a differential temporal approach to the induction of neuroprotection and the prevention of neurodegeneration.
    Frontiers in Aging Neuroscience 05/2015; 7(84). DOI:10.3389/fnagi.2015.00084 · 4.00 Impact Factor
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    • "Because impairment of autophagy only enhanced Cu toxicity, while inhibition of the proteasome enhanced both Cu and WT/A53T α-synuclein toxicity, our results suggest that α-synuclein exerts its effect primarily via modulation of the UPS. Autophagy is a catabolic process involved in cellular survival during conditions of environmental stress (Murrow and Debnath, 2013). In very few circumstances there is actual genetic-based evidence for a role of autophagy as a cell death pathway (Shen et al., 2012). "
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