Autophagy as a Stress-Response and Quality-Control Mechanism: Implications for Cell Injury and Human Disease
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 http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
- SourceAvailable from: Jakub Hanus
[Show abstract] [Hide abstract]
- "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. "
ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. The underlying mechanism of non-neovascular AMD (dry AMD), also named geographic atrophy (GA) remains unclear and the mechanism of retinal pigment epithelial (RPE) cell death in AMD is controversial. We review the history and recent progress in understanding the mechanism of RPE cell death induced by oxidative stress, in AMD mouse models, and in AMD patients. Due to the limitation of toolsets to distinguish between apoptosis and necroptosis (or necrosis), most previous research concludes that apoptosis is a major mechanism for RPE cell death in response to oxidative stress and in AMD. Recent studies suggest necroptosis as a major mechanism of RPE cell death in response to oxidative stress. Moreover, ultrastructural and histopathological studies support necrosis as major mechanism of RPE cells death in AMD. In this review, we discuss the mechanism of RPE cell death in response to oxidative stress, in AMD mouse models, and in human AMD patients. Based on the literature, we hypothesize that necroptosis is a major mechanism for RPE cell death in response to oxidative stress and in AMD.Ageing Research Reviews 09/2015; DOI:10.1016/j.arr.2015.09.002 · 4.94 Impact Factor
[Show abstract] [Hide abstract]
- "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. "
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
[Show abstract] [Hide abstract]
- "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). "
ABSTRACT: Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson's disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of WT or A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic cells and yeast in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways. Copyright © 2014. Published by Elsevier Inc.Neurobiology of Disease 12/2014; DOI:10.1016/j.nbd.2014.11.018 · 5.08 Impact Factor