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Therapeutic targeting of autophagy in neurodegenerative and infectious diseases.

Rubinsztein DC, Bento CF, Deretic V - J. Exp. Med. (2015)

Bottom Line: Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation.The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation.Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 OSP, England, UK dcr1000@cam.ac.uk vderetic@salud.unm.edu.

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Protective roles of autophagy in neurodegenerative and infectious diseases. A major role for autophagy in neurodegenerative and infectious diseases involves the clearance of toxic aggregate-prone proteins and infectious agents, respectively. However, it also exerts ancillary beneficial roles by controlling cell death and exacerbated inflammatory responses associated with these pathologies.
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fig2: Protective roles of autophagy in neurodegenerative and infectious diseases. A major role for autophagy in neurodegenerative and infectious diseases involves the clearance of toxic aggregate-prone proteins and infectious agents, respectively. However, it also exerts ancillary beneficial roles by controlling cell death and exacerbated inflammatory responses associated with these pathologies.

Mentions: Much of the pioneering work in the macroautophagy (henceforth referred to as autophagy in this review) field was initiated in yeast, where autophagy protects against cellular starvation. Although this role is conserved across evolution, more recent studies in mammalian systems have highlighted the importance of autophagy in diverse areas of physiology and disease. In this review, we will focus on the protective roles of autophagy in neurodegenerative and infectious diseases (Fig. 2). We will start by outlining the basic models where autophagosomes engulf and degrade neurodegeneration-associated aggregate-prone proteins or infectious agents. We will then describe possible mechanisms for enhancing the capture of such substrates to extents greater than would occur with bulk autophagy, during which one assumes there is random sequestration of cytoplasmic contents. We will extend the discussion of the roles of autophagy in these diseases by considering more complex consequences, including control of cell death, immunity, and inflammation. Although there are aspects that have been explored more in neurodegenerative diseases than infectious diseases, and vice versa, we believe that the opportunity to consider both in parallel will enable consideration of new hypotheses and cross-fertilization. We propose that the two main areas of overlap between the roles of autophagy in neurodegeneration and infectious disease are: (a) similarities in the shared usage of autophagic receptors in defending against pathology-inducing agents in both classes of disease (Birgisdottir et al., 2013), and (b) the now well-documented antiinflammatory action of autophagy (Deretic et al., 2013, 2015). This juxtaposition of autophagic roles in apparently distinct classes of diseases is a testament to the relevance of autophagy in cleansing the cellular interiors no matter what the disease context is, and is particularly timely in view of the explosion of data in the two fields. Finally, we will consider possible autophagy-related therapeutic strategies that may be of significance for these diseases, including the possibility of developing agents that may target both sets of conditions.


Therapeutic targeting of autophagy in neurodegenerative and infectious diseases.

Rubinsztein DC, Bento CF, Deretic V - J. Exp. Med. (2015)

Protective roles of autophagy in neurodegenerative and infectious diseases. A major role for autophagy in neurodegenerative and infectious diseases involves the clearance of toxic aggregate-prone proteins and infectious agents, respectively. However, it also exerts ancillary beneficial roles by controlling cell death and exacerbated inflammatory responses associated with these pathologies.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4493419&req=5

fig2: Protective roles of autophagy in neurodegenerative and infectious diseases. A major role for autophagy in neurodegenerative and infectious diseases involves the clearance of toxic aggregate-prone proteins and infectious agents, respectively. However, it also exerts ancillary beneficial roles by controlling cell death and exacerbated inflammatory responses associated with these pathologies.
Mentions: Much of the pioneering work in the macroautophagy (henceforth referred to as autophagy in this review) field was initiated in yeast, where autophagy protects against cellular starvation. Although this role is conserved across evolution, more recent studies in mammalian systems have highlighted the importance of autophagy in diverse areas of physiology and disease. In this review, we will focus on the protective roles of autophagy in neurodegenerative and infectious diseases (Fig. 2). We will start by outlining the basic models where autophagosomes engulf and degrade neurodegeneration-associated aggregate-prone proteins or infectious agents. We will then describe possible mechanisms for enhancing the capture of such substrates to extents greater than would occur with bulk autophagy, during which one assumes there is random sequestration of cytoplasmic contents. We will extend the discussion of the roles of autophagy in these diseases by considering more complex consequences, including control of cell death, immunity, and inflammation. Although there are aspects that have been explored more in neurodegenerative diseases than infectious diseases, and vice versa, we believe that the opportunity to consider both in parallel will enable consideration of new hypotheses and cross-fertilization. We propose that the two main areas of overlap between the roles of autophagy in neurodegeneration and infectious disease are: (a) similarities in the shared usage of autophagic receptors in defending against pathology-inducing agents in both classes of disease (Birgisdottir et al., 2013), and (b) the now well-documented antiinflammatory action of autophagy (Deretic et al., 2013, 2015). This juxtaposition of autophagic roles in apparently distinct classes of diseases is a testament to the relevance of autophagy in cleansing the cellular interiors no matter what the disease context is, and is particularly timely in view of the explosion of data in the two fields. Finally, we will consider possible autophagy-related therapeutic strategies that may be of significance for these diseases, including the possibility of developing agents that may target both sets of conditions.

Bottom Line: Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation.The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation.Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 OSP, England, UK dcr1000@cam.ac.uk vderetic@salud.unm.edu.

Show MeSH
Related in: MedlinePlus