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Review

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Autophagy and neurodegeneration
Rebecca A. Frake, … , Fiona M. Menzies, David C. Rubinsztein
Rebecca A. Frake, … , Fiona M. Menzies, David C. Rubinsztein
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):65-74. https://doi.org/10.1172/JCI73944.
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Autophagy and neurodegeneration

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Abstract

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.

Authors

Rebecca A. Frake, Thomas Ricketts, Fiona M. Menzies, David C. Rubinsztein

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Autophagy in cellular metabolism and cancer
Xuejun Jiang, … , Michael Overholtzer, Craig B. Thompson
Xuejun Jiang, … , Michael Overholtzer, Craig B. Thompson
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):47-54. https://doi.org/10.1172/JCI73942.
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Autophagy in cellular metabolism and cancer

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Abstract

Autophagy is a catabolic process mediated by incorporation of cellular material into cytosolic membrane vesicles for lysosomal degradation. It is crucial for maintaining cell viability and homeostasis in response to numerous stressful conditions. In this Review, the role of autophagy in both normal biology and disease is discussed. Emphasis is given to the interplay of autophagy with nutrient signaling through the ULK1 autophagy pre-initiation complex. Furthermore, related cellular processes utilizing components of the canonical autophagy pathway are discussed due to their potential roles in nutrient scavenging. Finally, the role of autophagy in cancer and its potential as a cancer therapeutic target are considered.

Authors

Xuejun Jiang, Michael Overholtzer, Craig B. Thompson

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Development of autophagy inducers in clinical medicine
Beth Levine, … , Milton Packer, Patrice Codogno
Beth Levine, … , Milton Packer, Patrice Codogno
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):14-24. https://doi.org/10.1172/JCI73938.
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Development of autophagy inducers in clinical medicine

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Abstract

Defects in autophagy have been linked to a wide range of medical illnesses, including cancer as well as infectious, neurodegenerative, inflammatory, and metabolic diseases. These observations have led to the hypothesis that autophagy inducers may prevent or treat certain clinical conditions. Lifestyle and nutritional factors, such as exercise and caloric restriction, may exert their known health benefits through the autophagy pathway. Several currently available FDA-approved drugs have been shown to enhance autophagy, and this autophagy-enhancing action may be repurposed for use in novel clinical indications. The development of new drugs that are designed to be more selective inducers of autophagy function in target organs is expected to maximize clinical benefits while minimizing toxicity. This Review summarizes the rationale and current approaches for developing autophagy inducers in medicine, the factors to be considered in defining disease targets for such therapy, and the potential benefits of such treatment for human health.

Authors

Beth Levine, Milton Packer, Patrice Codogno

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The functional and pathologic relevance of autophagy proteases
Álvaro F. Fernández, Carlos López-Otín
Álvaro F. Fernández, Carlos López-Otín
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):33-41. https://doi.org/10.1172/JCI73940.
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The functional and pathologic relevance of autophagy proteases

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Abstract

Autophagy is a well-conserved catabolic process essential for cellular homeostasis. First described in yeast as an adaptive response to starvation, this pathway is also present in higher eukaryotes, where it is triggered by stress signals such as damaged organelles or pathogen infection. Autophagy is characterized at the cellular level by the engulfment of portions of the cytoplasm in double-membrane structures called autophagosomes. Autophagosomes fuse with lysosomes, resulting in degradation of the inner autophagosomal membrane and luminal content. This process is coordinated by complex molecular systems, including the ATG8 ubiquitin–like conjugation system and the ATG4 cysteine proteases, which are implicated in the formation, elongation, and fusion of these autophagic vesicles. In this Review, we focus on the diverse functional roles of the autophagins, a protease family formed by the four mammalian orthologs of yeast Atg4. We also address the dysfunctional expression of these proteases in several pathologic conditions such as cancer and inflammation and discuss potential therapies based on their modulation.

Authors

Álvaro F. Fernández, Carlos López-Otín

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Immunologic manifestations of autophagy
Vojo Deretic, … , Santosh Chauhan, Michael Mandell
Vojo Deretic, … , Santosh Chauhan, Michael Mandell
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):75-84. https://doi.org/10.1172/JCI73945.
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Immunologic manifestations of autophagy

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Abstract

The broad immunologic roles of autophagy span innate and adaptive immunity and are often manifested in inflammatory diseases. The immune effects of autophagy partially overlap with its roles in metabolism and cytoplasmic quality control but typically expand further afield to encompass unique immunologic adaptations. One of the best-appreciated manifestations of autophagy is protection against microbial invasion, but this is by no means limited to direct elimination of intracellular pathogens and includes a stratified array of nearly all principal immunologic processes. This Review summarizes the broad immunologic roles of autophagy. Furthermore, it uses the autophagic control of Mycobacterium tuberculosis as a paradigm to illustrate the breadth and complexity of the immune effects of autophagy.

Authors

Vojo Deretic, Tomonori Kimura, Graham Timmins, Pope Moseley, Santosh Chauhan, Michael Mandell

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Pharmacologic agents targeting autophagy
Helin Vakifahmetoglu-Norberg, … , Hong-guang Xia, Junying Yuan
Helin Vakifahmetoglu-Norberg, … , Hong-guang Xia, Junying Yuan
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):5-13. https://doi.org/10.1172/JCI73937.
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Pharmacologic agents targeting autophagy

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Abstract

Autophagy is an important intracellular catabolic mechanism critically involved in regulating tissue homeostasis. The implication of autophagy in human diseases and the need to understand its regulatory mechanisms in mammalian cells have stimulated research efforts that led to the development of high-throughput screening protocols and small-molecule modulators that can activate or inhibit autophagy. Herein we review the current landscape in the development of screening technology as well as the molecules and pharmacologic agents targeting the regulatory mechanisms of autophagy. We also evaluate the potential therapeutic application of these compounds in different human pathologies.

Authors

Helin Vakifahmetoglu-Norberg, Hong-guang Xia, Junying Yuan

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mTOR: a pharmacologic target for autophagy regulation
Young Chul Kim, Kun-Liang Guan
Young Chul Kim, Kun-Liang Guan
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):25-32. https://doi.org/10.1172/JCI73939.
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mTOR: a pharmacologic target for autophagy regulation

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Abstract

mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism. mTOR regulates cell growth and proliferation in response to a wide range of cues, and its signaling pathway is deregulated in many human diseases. mTOR also plays a crucial role in regulating autophagy. This Review provides an overview of the mTOR signaling pathway, the mechanisms of mTOR in autophagy regulation, and the clinical implications of mTOR inhibitors in disease treatment.

Authors

Young Chul Kim, Kun-Liang Guan

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Autophagy: a druggable process that is deregulated in aging and human disease
Guido Kroemer
Guido Kroemer
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):1-4. https://doi.org/10.1172/JCI78652.
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Autophagy: a druggable process that is deregulated in aging and human disease

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Abstract

Autophagy (“self-eating”) constitutes one of the most spectacular yet subtly regulated phenomena in cell biology. Similarly to cell division, differentiation, and death, autophagy is perturbed in multiple diseases, in that excessive or deficient autophagy may contribute to pathogenesis. Numerous attempts have been launched to identify specific inducers or inhibitors of autophagy and to use them for the therapeutic correction of its deregulation. At present, several major disease categories (including but not limited to age-related, cardiovascular, infectious, neoplastic, neurodegenerative, and metabolic pathologies) are being investigated for pathogenic aberrations in autophagy and their pharmacologic rectification. Driven by promising preclinical results, several clinical trials are exploring autophagy as a therapeutic target.

Authors

Guido Kroemer

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Fibrosis: ultimate and proximate causes
Victor J. Thannickal, … , Amit Gaggar, Steven R. Duncan
Victor J. Thannickal, … , Amit Gaggar, Steven R. Duncan
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(11):4673-4677. https://doi.org/10.1172/JCI74368.
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Fibrosis: ultimate and proximate causes

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Abstract

Fibrotic disorders account for an increasing burden of disease-associated morbidity and mortality worldwide. Although numerous risk factors have been recognized, the etiologies of many of these clinical syndromes have not been identified, and they are often termed idiopathic or cryptogenic. Here, we provide an evolutionary perspective on fibrosis aimed at elucidating its etiopathogenesis. By asking the ultimate question of “why” this process evolved in multicellular organisms, we hope to uncover proximate explanations for “how” it causes disease in humans. We posit that physiological fibrosis-like reactions evolved as an essential process in host defense against pathogens and in normal wound healing. Based on this premise, we reason that pathological fibrosis is related to one or more of the following: unidentified infectious or noninfectious antigens, autoimmunity, impaired regenerative responses, and the antagonistically pleiotropic action of genes involved in wound healing or development. The importance of genetic susceptibility, epigenetics, aging, and the modern-day environment are highlighted. Consideration of both ultimate and proximate causation goes beyond philosophical cogitations, as it will better inform pathobiological mechanisms of disease and aid in the prevention and treatment of fibrotic diseases.

Authors

Victor J. Thannickal, Yong Zhou, Amit Gaggar, Steven R. Duncan

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Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9
Rajat M. Gupta, Kiran Musunuru
Rajat M. Gupta, Kiran Musunuru
Published October 1, 2014
Citation Information: J Clin Invest. 2014;124(10):4154-4161. https://doi.org/10.1172/JCI72992.
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Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9

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Abstract

The past decade has been one of rapid innovation in genome-editing technology. The opportunity now exists for investigators to manipulate virtually any gene in a diverse range of cell types and organisms with targeted nucleases designed with sequence-specific DNA-binding domains. The rapid development of the field has allowed for highly efficient, precise, and now cost-effective means by which to generate human and animal models of disease using these technologies. This review will outline the recent development of genome-editing technology, culminating with the use of CRISPR-Cas9 to generate novel mammalian models of disease. While the road to using this same technology for treatment of human disease is long, the pace of innovation over the past five years and early successes in model systems build anticipation for this prospect.

Authors

Rajat M. Gupta, Kiran Musunuru

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