Autophagy as a Therapeutic Target in Multiple Diseases: From Molecular Mechanisms to Drug Discovery

Autophagy as a Therapeutic Target in Multiple Diseases: From Molecular Mechanisms to Drug Discovery

Tuesday, September 25, 2012

The New York Academy of Sciences

Presented By

 

Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Alterations in autophagy are thought to play an important role in the pathogenesis of many diseases—for example, components of the autophagy pathway may be compromised in various central nervous system disorders. Studies have demonstrated that up-regulation of autophagy leads to decreased levels of toxic aggregate-prone proteins, and are beneficial in the context of various models of neurodegeneration. The autophagy machinery interfaces with many cellular stress-response pathways, and recent studies link defects in autophagy to chronic inflammation and immune-related processes. The regulation of autophagy in cancer cells can enhance tumor cell survival, yet can also suppress the initiation of tumor growth. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of anticancer therapies. This symposium will review molecular mechanisms of autophagy and its impairment across diverse diseases, and examines ongoing drug discovery strategies for modulating autophagy for therapeutic benefits.

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Agenda

* Presentation times are subject to change.


Tuesday September 25, 2012

8:30 AM

Registration and continental breakfast

9:00 AM

Introduction
Warren Hirst, PhD, Pfizer

9:10 AM

The Regulation of Macroautophagy
Daniel J. Klionsky, PhD, University of Michigan

9:55 AM

Autophagy in Nervous System and Neurodegeneration
Zhenyu Yue, PhD, Mount Sinai School of Medicine

10:40 AM

Coffee break

11:15 AM

Damage Control  - How the Pink1/Parkin Pathway can Regulate Removal of Impaired Mitochondria by Autophagy
Richard J. Youle, PhD, NINDS, NIH

12:00 PM

Role of Autophagy in Lung Cancer
Eileen P. White, PhD, Rutgers University

12:45 PM

Lunch break

1:30 PM

Identification of a Potent Autophagy-Inducing Peptide with Potential Therapeutic Benefits
Beth Levine, MD, University of Texas Southwestern Medical Center

2:15 PM

Autophagy Dysfunction in Alzheimer's Disease
Ralph A. Nixon, MD, PhD, Nathan Kline Institute

3:00 PM

Coffee break

3:30 PM

Drug Discovery Efforts in Autophagy - Therapeutic Targets for Alzheimer's and Parkinson's Diseases
Zdenek Berger, PhD, Pfizer

4:15 PM

Role of Chaperone Mediated Autophagy in Protein Quality Control
Ana Maria Cuervo, MD, PhD, Albert Einstein College of Medicine

5:00 PM

Networking reception

6:00 PM

Meeting Close

Speakers

Organizers

Zdenek Berger, PhD

Pfizer

Zdenek Berger is a senior scientist in the Neurodegeneration & Neurologic Diseases Department in the Pfizer Neuroscience Research Unit. He has been working in the neurodegeneration area for over 10 years. He currently leads a multidisciplinary group of scientists focused on 1) studying autophagy in the context of neurodegenerative disorders and 2) setting up screens to identify targets and small molecules enhancing autophagy-lysosomal pathway. He also devotes his time to other projects in neurodegeneration, including understanding the role of LRRK2 in Parkinson’s disease and developing LRRK2 kinase inhibitors as potential therapeutics. He participates in reviewing external opportunities in Pfizer and serves as an ad-hoc reviewer for several journals and Michael J. Fox Foundation. Zdenek obtained his PhD from the University of Cambridge where he worked on autophagy with David Rubinsztein, followed by post-doctoral fellowships at Mayo Clinic with Mike Hutton on tau and at Harvard Medical School on LRRK2. Zdenek has received prestigious scholarships and fellowships during this period, including EMBO fellowship, Parkinson’s disease Foundation fellowship, Lefler fellowship, Overseas Research Students Award, and Wellcome Trust Prize PhD Studentship. He has published 13 peer-reviewed publications and 3 reviews/book chapters, with over two thousand citations.

Mercedes Beyna, MS

Pfizer

Mercedes Beyna is a research scientist at Pfizer, where she is using biochemical and imaging approaches in the quest to understand the biology underlying various psychiatric disorders. She also performs molecular and cellular biology-based target identification and assay development functions. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Before joining pharmaceutical R&D, Mercedes held lab manager and senior lab technician positions at New York University (NYU). Her experience includes molecular neurobiology, synapse formation and plasticity, neurotrophin signaling, and developmental neurobiology areas. Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from NYU. As the Pfizer lead in the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences, she enjoys developing interesting and educational symposia.

Warren Hirst, PhD

Pfizer

Warren Hirst is an Associate Research Fellow and Group Leader in the Neurodegeneration & Neurologic Diseases Department in the Pfizer Neuroscience Research Unit. He currently leads a group of 9 scientists, including 4 Michael J Fox Foundation funded postdocs, focusing on two main projects: 1) Understanding the role of LRRK2 in Parkinson’s disease and leading the program to identify LRRK2 kinase inhibitors as potential therapeutics. 2) Determining the role of autophagy in neurodegenerative disorders, developing novel assays to identify small-molecule enhancers of autophagy and determination of their mechanism of action. Warren Hirst was previously in the Wyeth Neurodegeneration Research Department in Princeton where he led the Molecular Pharmacology group. At Wyeth Warren led the 5-HT1A receptor antagonist program team to successfully deliver a development candidate, which advanced to the clinic. Warren was also involved in a number of other programs for Alzheimer’s disease, including BACE, JNK3, PDE4 and H3 receptor antagonists, and was instrumental in developing the Parkinson’s disease strategy for the group. He joined Wyeth in 2004 from GlaxoSmithKline, Harlow, UK, where, among other responsibilities he led the 5-HT6 receptor antagonist program, successfully bringing forward a development candidate, which is currently in Phase 2 clinical trials. Warren received his undergraduate degree in Biochemistry from Imperial College of Science, Technology and Medicine, London. His Ph.D., at Imperial College and Guy’s Hospital, London, investigating the role of astrocytes in serotonergic neurotransmission, was sponsored by SmithKline Beecham and his extended visits to their research labs in Harlow were instrumental in determining his career in the pharma industry. Warren completed his PhD in 1996 and following 2 years postdoctoral research investigating the role of reactive astrocytes in CNS damage, at Imperial College, he joined SmithKline Beecham. He has published over 40 peer-reviewed articles.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Zdenek Berger, PhD

Pfizer

Zdenek Berger is a senior scientist in the Neurodegeneration & Neurologic Diseases Department in the Pfizer Neuroscience Research Unit. He has been working in the neurodegeneration area for over 10 years. He currently leads a multidisciplinary group of scientists focused on 1) studying autophagy in the context of neurodegenerative disorders and 2) setting up screens to identify targets and small molecules enhancing autophagy-lysosomal pathway. He also devotes his time to other projects in neurodegeneration, including understanding the role of LRRK2 in Parkinson’s disease and developing LRRK2 kinase inhibitors as potential therapeutics. He participates in reviewing external opportunities in Pfizer and serves as an ad-hoc reviewer for several journals and Michael J. Fox Foundation. Zdenek obtained his PhD from the University of Cambridge where he worked on autophagy with David Rubinsztein, followed by post-doctoral fellowships at Mayo Clinic with Mike Hutton on tau and at Harvard Medical School on LRRK2. Zdenek has received prestigious scholarships and fellowships during this period, including EMBO fellowship, Parkinson’s disease Foundation fellowship, Lefler fellowship, Overseas Research Students Award, and Wellcome Trust Prize PhD Studentship. He has published 13 peer-reviewed publications and 3 reviews/book chapters, with over two thousand citations.

Ana Maria Cuervo, MD, PhD

Albert Einstein College of Medicine

Ana Maria Cuervo is a Professor in the Departments of Developmental and Molecular Biology and of Medicine of the Albert Einstein College of Medicine, co-director of the Einstein Institute for Aging Studies. She obtained her M.D. degree and a Ph.D. in Biochemistry and Molecular biology from the University of Valencia (Spain) in 1990 and 1994, respectively, and received postdoctoral training at Tufts University, Boston. In 2002, she started her laboratory at the Albert Einstein College of Medicine, where she continues her studies in the role of protein-degradation in neurodegenerative diseases and aging. Dr. Cuervo has been invited to present the Robert R. Konh Memorial Lecture, the NIH Director’s Lecture and the Roy Walford Endowed Lecture and she was the recipient of the 2005 P. Benson Award in Cell Biology, the 2005/8 Keith Porter Fellow in Cell Biology, the 2006 Nathan Shock Memorial Lecture Award and the 2008 Vincent Cristofalo Rising Start in Aging Award. She is currently co-Editor-in-Chief of Aging Cell, associate editor of Autophagy, and member of the NIH/NIA Scientific Council.

Daniel J. Klionsky, PhD

University of Michigan

Dr. Daniel J. Klionsky was an undergraduate at UCLA, received his Ph.D. from Stanford University, and was a Helen Hay Whitney postdoctoral fellow at the California Institute of Technology. Dr. Klionsky was a Professor of Microbiology at the University of California, Davis until 2000 and held a Guggenheim Fellowship in 1997-1998. He is currently the Alexander G. Ruthven Professor of Life Sciences at the University of Michigan, Ann Arbor. Dr. Klionsky is highly committed to excellence in teaching. In 2003 he received the National Science Foundation Director's Award for Distinguished Teaching Scholars, which recognizes career contributions in both teaching and research, and in 2006, the National Academies of Science named him an Education Mentor. Dr. Klionsky's research focuses on protein targeting, organelle biogenesis and autophagy in baker's yeast. Dr. Klionsky is the founding Editor-in-Chief of the journal Autophagy, and he was elected a Fellow of the AAAS in 2009.

Beth Levine, MD

University of Texas Southwestern Medical Center

Dr. Levine is internationally recognized as a leading authority in the field of virus-host interactions and in the field of autophagy. Dr. Levine received an A.B. from Brown University, an M.D. from Cornell University Medical College, and completed her postdoctoral training in Infectious Diseases/Viral Pathogenesis at the Johns Hopkins University School of Medicine. In 1993, she joined the faculty at Columbia University College of Physicians & Surgeons where she became Associate Professor of Medicine. In 2004, she became the Jay P. Sanford Professor and Chief of the Division of Infectious Diseases at UT Southwestern Medical Center. In 2011, she became the Director of a newly created Center for Autophagy Research at UT Southwestern and the Charles Cameron Sprague Distinguished Chair in Biomedical Science. Since 2008, she has been a Howard Hughes Medical Institute Investigator. Dr. Levine’s laboratory has made fundamental discoveries that have helped to open up a new field of biomedical research – the role of autophagy in human health and disease. Her laboratory identified the mammalian autophagy gene, beclin 1, and defined a role for beclin 1 and the autophagy pathway in tumor suppression, antiviral immunity, development, cell death regulation, lifespan regulation, and most recently, in exercise-induced metabolic effects.

Ralph A. Nixon, MD, PhD

Nathan Kline Institute

Professor of Psychiatry and Cell Biology, Director of the Comprehensive Center on Brain Aging and the Silberstein Alzheimer’s Institute at New York University Langone Medical Center; Director of Research and the Center for Dementia Research, Nathan Kline Institute.

Dr. Nixon received his PhD from Harvard University, MD from University of Vermont, and training in medicine and psychiatry at Massachusetts General Hospital. He is a Fellow of the American College of Neuropsychopharmacology. Dr. Nixon’s pioneering research first established the importance of proteases and defective proteolytic systems in the pathogenesis of Alzheimer’s disease and has identified new therapeutic approaches for the disease. He has published over 250 scientific papers and is the holder of nine active and pending patents. He currently serves as Chairman of the Medical and Scientific Advisory Council (MSAC) of the national Alzheimer’s Association and is also a member of the Association’s National Board of Directors. He serves on the CMND Study Section at NIH and on the Governor’s Commission on Alzheimer’s Disease for New York State. Dr. Nixon’s awards include the Leadership and Excellence in Alzheimer Research, MERIT, and Academic Career Leadership Awards from the National Institutes of Health, and the Zenith and Temple Discovery Awards from the Alzheimer’s Association.

Eileen P. White, PhD

Rutgers University

Dr. Eileen White received a B.S. from Rensselaer Polytechnic Institute and a Ph.D. in Biology from SUNY Stony Brook. She was a Damon Runyon Postdoctoral fellow in the laboratory of Dr. Bruce Stillman at Cold Spring Harbor Laboratory. She is currently the Associate Director for Basic Science at the Cancer Institute of New Jersey (CINJ), Professor of Molecular Biology and Biochemistry at Rutgers University, and Adjunct Professor of Surgery at UMDNJ. Dr. White has served on the Board of Scientific Counselors of the National Cancer Institute (NCI) and the Board of Directors of the American Association for Cancer Research (AACR). She has received a MERIT Award from the NCI, an Investigatorship from the Howard Hughes Medical Institute (HHMI), the Red Smith Award from the Damon Runyon Cancer Research Foundation, an Achievement Award from the International Cell Death Society, and a Career Award from the European Cell Death Organization. Dr. White is also an elected Fellow of the American Society of Microbiology (ASM) and the American Association for the Advancement of Science (AAAS). Dr. White currently serves on the Scientific Review Boards for the Starr Cancer Consortium and the Cancer Prevention Research Institute of Texas (CPRIT), and is a member of the Board of Scientific Advisors for the AACR. Dr. White is a member of Dr. Varmus’s “Big Questions Project” to guide future of the NCI. Editorial Boards memberships include of Genes & Development, Cancer & Metabolism, Oncogene, Cancer Prevention Research, Molecular Cancer Research, Autophagy, Cell Death and Disease and Cancer Discovery.

Richard J. Youle, PhD

NINDS

Dr. Youle received an A.B. degree from Albion College and his Ph.D. degree from the University of South Carolina where he worked on the protein toxin ricin. He joined the lab of David Neville at the National Institute of Mental Health for postdoctoral work on the engineering of cell-type-specific protein toxins. He joined the Surgical Neurology Branch of NINDS in 1985 as a principal investigator where he has developed new treatment strategies for brain tumors. His lab is now exploring the molecular mechanisms of programmed cell death and the role of mitochondria in neurodegenerative disorders.

Zhenyu Yue, PhD

Mount Sinai School of Medicine

After PhD training in biochemistry and cell biology at UMDNJ/Rutgers and Postdoc work in mouse genetic study of neurodegeneration, Dr. Yue became an independent investigator at Mount Sinai School of Medicine. He is now an Associate Professor, head of the Molecular and Cellular Neurobiology Laboratory in Department of Neurology and Neuroscience, Friedman Brain Institute at Sinai. Dr Yue has been a pioneer in autophagy research in central nervous system and edited the book “Autophagy of the Nervous System”. The long-term goal of the Yue Laboratory is to understand cellular and molecular mechanisms of autophagy regulation in the CNS and neurodegeneration. They also endeavor to investigate formation and degradation of disease protein aggregates, develop genetic models for neurodegenerative diseases and identify biological and chemical probes for modifying disease process. Dr Yue’s primary research areas include Parkinson’s, Huntington’s and Alzheimer’s diseases. Dr. Yue received research awards and grants from Michael J Fox Foundation for Parkinson Research, Bachmann-Strauss Dystonia and Parkinson Foundation, CHDI Foundation, and NIH/NINDS.

 

 

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Abstracts

The Regulation of Macroautophagy
Daniel J. Klionsky, University of Michigan

Over thirty genes have been identified in yeast that are specific to macroautophagy, and homologs have been identified for many of these genes in higher eukaryotes. Although some of the detailed mechanism of macroautophagy has been elucidated, there are still many questions concerning the molecular basis of the pathway that remain unanswered. For example, how is the initial sequestering compartment, the phagophore, nucleated? What is the origin of the membrane used for expansion of the phagophore to form the autophagosome? What are the roles of the various autophagy-related proteins in the process of autophagosome biogenesis?
 
Macroautophagy occurs at basal levels, but can be induced in response to different types of stress. Recent work connects macroautophagy to a range of diseases in humans, and there is a potential for modulating macroautophagy for therapeutic purposes; however, such use will require careful control of macroautophagic induction because excessive macroautophagy may lead to cell death. Thus, either too little or too much of this process can have detrimental consequences. For many years it has been known that macroautophagy is regulated by the Tor kinase; however, surprisingly few details of the regulatory mechanism have been elucidated. In addition, macroautophagy responds to a range of stimuli, and the network that connects these regulatory pathways is complex.
 
We have been analyzing the regulation of macroautophagy in Saccharomyces cerevisiae. One of the central autophagy-related (Atg) proteins is Atg8, a ubiquitin-like protein that is conjugated to phosphatidylethanolamine. The amount of Atg8 determines the size of autophagosomes; however, the factors controlling the expression of ATG8 have not been determined. Recently, we have been analyzing the regulation of ATG8 transcription. Because of the conserved nature of this process, the insight we gain from understanding regulation in the genetically tractable yeast system will provide additional direction for analyses in higher eukaryotes.
 
Supported by NIH Public Health Service grant GM53396

Autophagy in Nervous System and Neurodegeneration
Zhenyu Yue, Mount Sinai School of Medicine

Autophagy is a cell self-eating pathway involving delivery and digestion of cellular content in lysosomes. While autophagy is responsible for the turnover of aggregate-prone proteins, macromolecular complexes and damaged cellular organelles (e.g. mitophagy), the precise mechanism of autophagy process and regulation in the nervous system and its role in the neurodegenerative disease remain largely elusive. We have investigated in vivo function of key autophagy genes in the CNS neurons. Our studies demonstrate the neuroprotective role of autophagy in the clearance of ubiquitinated proteins aggregates and prevention of axonopathies and neurodegeneration. We find that different neurons differ in their response to the disruption of autophagy and the study suggests different vulnerability of neurons to autophagy related pathogenesis. Moreover, autophagy regulates the levels of neurological disease-related proteins, many of which form oligomers/aggregates that are neurotoxic; examples include polyQ-containing proteins such as huntingtin in Huntington disease, α-synuclein in Parkinson's disease, tau in tauopathies, and Aβ/APP metabolites in Alzheimer's disease. I will present our work that shows intersection of autophagy with cellular pathways that regulate disease protein homeostasis, and therefore, autophagy is an important disease-modifying mechanism. I will also discuss our effort in developing autophagy-enhancing therapeutics for the purpose of treating neurodegenerative diseases.

Damage Control — How the Pink1/Parkin Pathway can Regulate Removal of Impaired Mitochondria by Autophagy
Richard J. Youle, NINDS, NIH

The products of two genes mutated in autosomal recessive forms of Parkinson's disease, Pink1 and Parkin, have been identified in Drosophila to work in the same pathway to maintain healthy flight muscles and dopaminergic neurons. PINK1 is a kinase located on mitochondria whereas Parkin is an E3 ubiquitin ligase normally located in the cytosol. Upon mitochondrial damage Pink1 recruits cytosolic Parkin to mitochondria to mediate mitophagy suggesting in mammalian cells that Pink1 can work in the same pathway as Parkin to mediate mitochondrial quality control. PINK1 appears to be constitutively imported to the inner mitochondrial membrane of healthy mitochondria and degraded by PARL and downstream proteases. When import is impaired by mitochondrial damage PINK1 accumulates on the outer mitochondrial membrane where it can recruit Parkin from the cytosol. This sensing mechanism allows the detection and selective removal of damaged mitochondria within a cell. We have found that PINK1 on the outer mitochondrial membrane is stably bound to the TOM complex. However, the TOM complex does not appear crucial for PINK1 to recruit Parkin as inducible targeting of PINK1 to peroxisomes that lack the TOM complex mediates Parkin recruitment to peroxisomes and induces pexophagy. If mitochondria recover membrane potential PINK1 is rapidly reimported into mitochondria and degraded suggesting that PINK1 binding to TOM allows rapid downregulation of PINK1 and salvage of mitochondria from the mitophagy pathway.

Role of Autophagy in Lung Cancer
Eileen P. White, Rutgers University

Autophagy, or cellular self-digestion, degrades and recycles proteins and organelles and is an adaptive stress response that supports cellular metabolism and survival. Oncogenic Ras upregulates basal autophagy, and Ras-transformed cell lines require autophagy to maintain mitochondrial health, survive stress, and efficiently form engrafted tumors. To explore the role of autophagy in initiation and progression of spontaneously occurring Ras-driven tumors, the essential autophagy gene, autophagy-related-7, atg7, was deleted concurrently with K-rasG12D activation in mouse lung in a model of non-small-cell lung cancer (NSCLC). Here we show that deficiency in atg7 did not alter early tumor growth, but led to the accumulation of autophagy substrates and dysfunctional mitochondria, and resulted in eventual tumor atrophy. Although atg7 deletion slowed tumor growth, it did not delay death, which resulted from fulminant pulmonary inflammation rather than ablation of the lung by tumor. To explore the cause of the impaired tumor growth and enhanced inflammation in atg7-deficient mice, we analyzed the metabolome of Ras-driven tumors, finding specific depletion of adenosine in the absence of autophagy. Tumor-produced ATP is degraded extracellularly to adenosine, which interacts with receptors to promote tumor growth by acting as a paracrine signal that suppresses the anti-tumor immune response and activates oncogenic signal transduction. Adenosine receptor antagonism suppressed growth of wild type but not autophagy-deficient tumors, indicating that autophagy promotes tumor growth in part by supporting extracellular levels of the anti-inflammatory compound adenosine. Blocking autophagy or adenosine signaling are novel approaches to lung cancer treatment.

Identification of a Potent Autophagy-Inducing Peptide with Potential Therapeutic Benefits
Beth Levine, University of Texas Southwestern Medical Center

The lysosomal degradation pathway of autophagy plays a crucial role in defense against infection, neurodegenerative disorders, cancer, and aging, and impairment of autophagy may partially contribute to host susceptibility to these diseases. Accordingly, novel pharmacological agents that increase autophagy may have broad clinical applications. One approach to developing such agents is to learn from the strategies employed by microbial virulence proteins to manipulate host autophagy. Previously, the HIV pathogenic protein, Nef, was shown to interact with an essential autophagy protein, Beclin 1, and modulate autophagy. Our laboratory mapped the region of Beclin 1 required for binding to Nef, and identified 18 amino acids within the evolutionarily conserved domain of Beclin 1 that is essential for the Nef-Beclin 1 interaction. We found that a fusion peptide, Tat-Beclin 1, consisting of the Tat protein transduction domain and a derivative of this region of Beclin 1, was a potent inducer of autophagy in cultured mammalian cells as well as in vivo in mice. We identified a cellular target of the Tat-Beclin 1-peptide that interacts with full-length Beclin 1 and functions as a newly identified negative regulator of autophagy. Consistent with the known role of autophagy in clearing protein aggregates and restricting the replication of some intracellular pathogens, the Tat-Beclin 1 autophagy-inducing peptide decreased huntingtin protein aggregates in cells expressing mutant huntingtin and decreased the in vitro replication of chikungunya virus, West Nile virus, HIV, and Listeria monocytogenes. Moreover, Tat-Beclin 1 treatment improved clinical outcomes in mice infected with chikungunya and West Nile virus. Thus, through characterizing a domain of Beclin 1 that interacts with HIV-1 Nef, we have identified a novel regulator of the autophagy-inducing Beclin 1/Class III PI3K complex and have identified an autophagy-inducing peptide that has potential efficacy in the treatment of certain clinical diseases.

Autophagy Dysfunction in Alzheimer's Disease
Ralph A. Nixon, MD, PhD, Nathan Kline Institute

Neurons are particularly vulnerable to dysfunction within the endocytic and autophagic pathways (the "lysosomal network") because of their extreme polar shapes and high levels of vesicular trafficking. In the extensive neuritic dystrophy of Alzheimer's disease (AD), which is a pathological hallmark of the disease, autophagic vacuoles containing incompletely digested proteins selectively accumulate in focal axonal swellings, reflecting defects in both autophagy and axonal transport. Growing evidence indicates that this massive "storage" of waste proteins in neurons, reminiscent of lysosomal storage diseases, mainly reflects a failure of lysosomal proteolytic clearance of autophagic substrates. Compounding the problem is a moderate induction of autophagy, as evidenced by elevated neuronal expression of autophagy genes measured in CA1 hippocampal neurons of the AD brain in mRNA profiling analyses.

Impaired lysosomal proteolysis is the likely basis for defects in both autophagy and axonal transport leading to the neuritic dystrophy of AD. In living primary cortical neurons expressing fluorescence-tagged markers, LC3-positive autophagosomes in axons rapidly acquired endo-lysosomal markers (Rab7 and LAMP1), underwent retrograde movement, and fused with bi-directionally moving lysosomes that are increasingly numerous at proximal axon levels and in the perikaryon. Disrupting lysosomal proteolysis by either inhibiting cathepsins directly or suppressing lysosomal acidification slowed the axonal transport of autophagy-related organelles but not other organelles and caused their selective accumulation within dystrophic axonal swellings that display various AD-like characteristics. Restoration of lysosomal proteolysis cleared accumulated autophagic substrates and reversed the axonal dystrophy.

Defective lysosomal proteolysis is one facet of a continuum of lysosomal system deficits in AD that begin to be evident even prior to amyloid-ß deposition and are driven in part by AD-related genes. The AD-related gene presenilin1 (PS1) is essential for lysosomal proteolysis and autophagy and plays a novel role in lysosome acidification required for protease activation. In cells lacking PS1, including neurons in PS1 mice, a failure to deliver the proton pump vATPase to lysosomes results in autophagy failure. PS1 mutations causing familial AD also confer partial loss of these same functions in fibroblasts from PS-FAD patients and in neurons of AD model mice. Lysosomal and autophagy dysfunction also develops in sporadic AD and in AD mouse models driven in part by other AD-related genes, including amyloid precursor protein and apolipoprotein Ε. Mutations or polymorphisms of these genes that increase AD risk interfere with cell signaling, markedly upregulate endocytosis, placing stress on autophagy/lysosomal mechanisms by increasing delivery of substrates to this system. Supporting the pathogenic significance of lysosomal system dysfunction in AD, we found that partially restoring deficient autophagy in the CRND8 mouse model of AD by genetically manipulating lysosomal protease activities substantially ameliorates lysosomal pathology, amyloid burden, neuritic dystrophy, and memory deficits.

These findings and others indicate that the same AD genetics that implicate Aß in AD also implicate antecedent lysosomal system dysfunction as a mechanism that both cripples neuronal functions critical for synaptic plasticity and neuron survival and promotes accumulation of toxic proteins, including Aß and tau.

This work is supported by the National Institute on Aging P01 AG01 7617

Drug Discovery Efforts in Autophagy - Therapeutic Targets for Alzheimer's and
Parkinson's Diseases.

Zdenek Berger, PhD, Pfizer

Autophagy represents a major route for degradation of cellular proteins and is important for turnover of aggregated proteins and organelles. Previous studies demonstrated that enhanced autophagy is associated with both decreased levels of toxic aggregate-prone proteins and reduced toxicity in the context of various models of neurodegeneration. The most commonly used enhancer of autophagy is rapamycin, an allosteric mTOR inhibitor. Recent screens have identified new putative autophagy enhancers, potentially offering a wealth of different targets. However, many of these different compounds and targets remain to be validated. In addition, their relative potencies have not been comprehensively determined, in part due to a lack of reliable and quantitative autophagy assays. We have generated cell based autophagy assays that measure autophagy flux. I will present an analysis of previously suggested autophagy enhancers and compare their relative potencies. This allows one to prioritize promising targets and small molecules that have robust effects.

In order to achieve up-regulation of autophagy in human subjects, it is important to understand any potential alterations of this pathway in the human disease. Changes in the autophagy pathway have been observed in brain tissues from patients with Alzheimer's and Parkinson's diseases, raising the possibility that the aggregate-prone proteins may alter autophagy. However, there are conflicting results from prior studies examining effects of a-synuclein on autophagy. In addition, while autophagy pathology has been carefully examined in APP transgenics, little is known about effects of tau or of tau pathology on autophagy. I will present analysis of effects of both mutant a-synuclein and mutant tau on autophagy flux, both in primary neurons and transgenic animals. Our results suggest that aggregate-proteins likely have complex effects on autophagy and that these should be carefully considered prior to any therapeutic intervention and also target selection.

Role of Chaperone Mediated Autophagy in Protein Quality Control
Ana Maria Cuervo, Albert Einstein College of Medicine

All types of autophagy fulfill two important functions in mammalian cells, serving both as an alternative source of energy, when nutrients are scarce, and as an efficient mechanism for the removal of any intracellular damaged structures. In this talk, I will focus on a selective form of autophagy, known as chaperone-mediated autophagy (CMA) and the connections between this pathway and cellular quality control.
 
CMA mediates selective targeting of soluble cytosolic proteins to lysosomes for their degradation. CMA is active in most cell types in mammalians but its activity varies depending on cellular conditions. Maximal activation of this pathway occurs during stress or in conditions leading to increased amount of misfolded/damaged proteins. Degradation via this pathway requires a set of cytosolic and lysosomal chaperones and a receptor protein at the lysosomal membrane, the lysosome-associated membrane protein type 2A (LAMP-2A). The limiting step of this type of autophagy is the binding of substrates to LAMP-2A. We have found that changes in the levels and organization of LAMP-2A at the lysosomal membrane underlie the molecular basis for the regulation of CMA. Two lysosomal chaperones, hsc70 and hsp90, are critical regulators of the higher order organization of LAMP-2A and the assembly of the translocation complex.
 
In recent years, the better molecular characterization of CMA has considerably advanced our understanding of the physiological role of this pathway and the consequences of its malfunctioning in the pathogenesis of detrimental human pathologies, such as cancer, neurodegenerative and metabolic diseases.
 
In this talk, I will describe some of the recent findings on the interplay between pathogenic proteins and CMA. We are addressing this interaction as a two-side relationship: 1) the contribution of CMA to the removal of pathogenic proteins and 2) the effect that pathogenic proteins can exert on CMA activity. Lastly, I will comment on the functional decline of CMA with age and the reasons behind this decline.

 

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