Downloaded from http cshperspectives cshlp org at BRANDEIS UNIV on August 14 2012 Published by Cold Spring Harbor Laboratory Press Proteostasis and Movement Disorders Parkinson s Disease and Amyotrophic Lateral Sclerosis Daryl A Bosco Matthew J LaVoie Gregory A Petsko and Dagmar Ringe Cold Spring Harb Perspect Biol 2011 doi 10 1101 cshperspect a007500 originally published online August 15 2011 Subject Collection Protein Homeostasis Protein Folding and Quality Control in the ER Kazutaka Araki and Kazuhiro Nagata Protein Misfolding and Retinal Degeneration Radouil Tzekov Linda Stein and Shalesh Kaushal Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases Progress and Prognosis Susan L Lindquist and Jeffery W Kelly ER Stress and Its Functional Link to Mitochondria Role in Cell Survival and Death Jyoti D Malhotra and Randal J Kaufman Alzheimer s Disease Dennis J Selkoe Prions David W Colby and Stanley B Prusiner Huntington s Disease Steven Finkbeiner Integrating Protein Homeostasis Strategies in Prokaryotes Axel Mogk Damon Huber and Bernd Bukau Protein Folding and Quality Control in the ER Kazutaka Araki and Kazuhiro Nagata Protein Solubility and Protein Homeostasis A Generic View of Protein Misfolding Disorders Michele Vendruscolo Tuomas P J Knowles and Christopher M Dobson Proteostasis and Movement Disorders Parkinson s Disease and Amyotrophic Lateral Sclerosis Daryl A Bosco Matthew J LaVoie Gregory A Petsko et al Quality Control of Mitochondrial Proteostasis Michael J Baker Takashi Tatsuta and Thomas Langer Cellular Strategies of Protein Quality Control Bryan Chen Marco Retzlaff Thomas Roos et al The Stress of Protein Misfolding From Single Cells to Multicellular Organisms Tali Gidalevitz Veena Prahlad and Richard I Morimoto Aging as an Event of Proteostasis Collapse Rebecca C Taylor and Andrew Dillin Hepatic Fibrosis and Carcinogenesis in a1 Antitrypsin Deficiency A Prototype for Chronic Tissue Damage in Gain of Function Disorders David H Perlmutter and Gary A Silverman For additional articles in this collection see http cshperspectives cshlp org cgi collection Copyright 2011 Cold Spring Harbor Laboratory Press all rights reserved Downloaded from http cshperspectives cshlp org at BRANDEIS UNIV on August 14 2012 Published by Cold Spring Harbor Laboratory Press Proteostasis and Movement Disorders Parkinson s Disease and Amyotrophic Lateral Sclerosis Daryl A Bosco1 Matthew J LaVoie2 Gregory A Petsko2 3 and Dagmar Ringe2 3 1 Department of Neurology University of Massachusetts Medical Center Worcester Massachusetts 01655 2 Department of Neurology and Center for Neurologic Diseases Harvard Medical School and Brigham Women s Hospital Boston Massachusetts 02115 3 Department of Biochemistry and Rosenstiel Basic Medical Sciences Research Center Brandeis University Waltham Massachusetts 02454 Correspondence ringe brandeis edu Parkinson s disease PD is a movement disorder that afflicts over one million in the U S amyotrophic lateral sclerosis ALS or Lou Gehrig s disease is less prevalent but also has a high incidence The two disorders sometimes present together making a comparative study of interest Both ALS and PD are neurodegenerative diseases and are characterized by the presence of intraneuronal inclusions however different classes of neurons are affected and the primary protein in the inclusions differs between the diseases and in some cases is different in distinct forms of the same disease These observations might suggest that the more general approach of proteostasis pathway alteration would be a powerful one in treating these disorders Examining results from human genetics and studies in model organisms as well as from biochemical and biophysical characterization of the proteins involved in both diseases we find that most instances of PD can be considered as arising from the misfolding and self association to a toxic species of the small neuronal protein asynuclein and that proteostasis strategies are likely to be of value for this disorder For ALS the situation is much more complex and less clear cut the available data are most consistent with a view that ALS may actually be a family of disorders presenting similarly but arising from distinct and nonoverlapping causes including mislocalization of some properly folded proteins and derangement of RNA quality control pathways Applying proteostasis approaches to this disease may require rethinking or broadening the concept of what proteostasis means INTRODUCTION NEUROLOGIC DISORDERS OF MOVEMENT ore than two million Americans are believed to suffer from some form of neurodegenerative movement disorder the total M cost of which is estimated to exceed 10 billion annually Because no society on earth is spared the effects of these crippling diseases the figures for other countries are similar adjusted for population differences The neurodegenerative Editors Richard I Morimoto Dennis Selkoe and Jeff Kelly Additional Perspectives on Protein Homeostasis available at www cshperspectives org Copyright 2011 Cold Spring Harbor Laboratory Press all rights reserved doi 10 1101 cshperspect a007500 Cite this article as Cold Spring Harb Perspect Biol 2011 3 a007500 1 Downloaded from http cshperspectives cshlp org at BRANDEIS UNIV on August 14 2012 Published by Cold Spring Harbor Laboratory Press D A Bosco et al diseases Parkinson s disease PD and amyotrophic lateral sclerosis ALS or Lou Gehrig s disease are the most important of the movement disorders from a proteostasis perspective ALS is often classified separately as a motor neuron disease but there are a number of reasons for considering them together of which perhaps the most important is that the two sometimes present together as in the Parkinsonism dementia complex of Guam Lytico bodig This movement disorder occurs among the Chamorro populations of Guam and the Mariana Islands and is frequently accompanied by a motor neuron disease resembling ALS The course of the disease is rapid with death typically occurring within 5 years Steele 2005 PD is the second most common neurodegenerative disease after Alzheimer s disease AD estimates of prevalence range to over one million in the U S Although ALS is considered a so called orphan disease because of its relatively low prevalence around 30 000 cases in the United States the annual incidence of ALS is actually closer to that of Parkinson s 6000 for ALS versus 60 000 for PD in the United
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