Cshperspect-PRT-FM I-Viii 1..8

Preface

HE EFFICIENT FUNCTIONING OF THE PROTEOME is fundamental to all cellular processes, and conse- Tquently it is of central importance to the health of the cell and lifespan of the organism. Protein homeostasis, or proteostasis, corresponds to the molecular interactions of each polypeptide within the expressed proteome of each cell and ensures its proper expression, folding, translocation, and clearance. For each protein, this is achieved by a network comprising molecular chaperones, transport machineries, the ubiquitin-dependent proteasome, and autophagic activities that function in concert under optimal conditions to orchestrate proteome health. Stress and aging, however, challenge the proteostasis network to maintain balance, and in certain cases become limiting, thus increasing the risk of cellular pathology and disease. Although much of the information required for the folding of polypeptide chains into functional three-dimensional native conformations is encoded in the primary sequence, it is clear that the cellular environment controls the stability of the fold and consequently the function of all proteins. Moreover, the folding and stability of the native state is not only challenged by the crowded cellular environment, but it is also strongly influenced by expressed polymorphisms and a myriad of posttranslational modifications that accumulate with age. These contribute to the pool of metastable proteins that readily misfold, aggregate, and in turn amplify the stress of misfolded proteins. The composition of the proteome, therefore, is a dynamic property of the cell. Proteostasis, however, is regulated both in a cell-autonomous manner to ensure that each cell can achieve an optimal state and by cell-nonautonomous control in metazoans to achieve interdependence among cells and tissues. Collectively, these events, through proteome protective and quality control mechanisms, determine the health of the cell and the lifespan of the organism. Stress represents a prominent challenge to proteostasis that cannot be predicted but for which the cell must be prepared. The challenges incurred during aging—acute stress such as heat shock, oxidants, and metabolic stress or chronic stress when mutant and damaged proteins are expressed—lead to a growing burden of misfolded and damaged proteins. There is increasing evidence to support the hypothesis that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when uncorrected, initiates a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation. These include many of the most challenging diseases to affect us, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), metabolic diseases, and cancer. Although each disease has a distinctive clinical profile with characteristic tissue vulnerability and age-dependent onset, they all have in common the expression of one or more aggregation-prone proteins. This volume has been written to serve diverse purposes: for an advanced course in cell biology, biochemistry, or the molecular basis of disease or as a comprehensive “state-of-the-art” volume of topics across the breadth of the field. Consequently, this volume will be invaluable for graduate students and postdoctoral fellows, as well as more advanced researchers, and for those entering from intersecting disciplines. Finally, as this volume represents an effort to be comprehensive, the individual chapters should be useful for those looking for a critical assessment of specific domains. Protein Homeostasis addresses the remarkable story of the life of proteins: from their intrinsic folding properties to the cellular events of synthesis, folding, transport, and clearance and responses to stress, aging, and disease. The topics covered in this volume reflect the current state of the field.

It flows seamlessly from the physical biochemistry of protein folding, to protein folding in diverse cells and tissues, to a plethora of diseases of protein conformation, and closes on the development of novel therapeutic strategies. This story has been told over installments, with each of three previous volumes from Cold Spring Harbor Laboratory Press providing increasing knowledge and new insights into the biology of molecular chaperones, the heat shock and unfolded protein responses, and, more recently, diseases of protein conformation. This volume traces its roots back to Heat Shock—From Bacteria to Man (1982), Stress Proteins in Biology and Medicine (1990), and The Biology of Heat Shock Proteins and Molecular Chaperones (1994). Each book and the chapters therein follow the discoveries that have propelled this field from the initial observations on the heat shock response in Drosophila salivary glands and tissue culture cells, the identification of the heat shock proteins and cloning of highly conserved heat shock genes, and the demonstration of the central roles for heat shock factors in transcriptional regulation of the heat shock response to experiments that revealed the remarkable properties and function of the heat shock proteins and molecular chaperones in protein folding and suppression of misfolding. Emerging from the first Cold Spring Harbor Laboratory meeting in 1982 were the tantalizing hints that the stress response and heat shock proteins could be relevant to human diseases. The molecular chaperone concept was on the horizon but had yet to be supported by experimental evidence. However, it was already clear that the induction of heat shock proteins by a myriad of stress conditions causes a fundamental reprogramming of the cell, leading to a cytoprotective state that provides not only protection against the same and more extreme stress exposures but also cross-protection against many other forms of environmental and physiological stress. Some 30 years later, the field has flourished, and the stories have become even more compelling. We now understand that the biochemical and biophysical properties of a large family of molecular chaperones that regulate folding, prevent misfolding, and direct damaged proteins to the degradative machinery prevent the accumulation of damaged proteins. This convergence, together with the fundamental understanding that protein damage has serious consequences to the cell, is further amplified with the growing appreciation that aging represents a significant risk factor for proteome stability. An emphasis of this new volume is the evidence that proteostatic deficiencies in neurodegenerative disease and other diseases of protein conformation that interfere with protein stability and function can be suppressed by enhancing the activities of chaperones and restoring the proteasome and autophagy. Whether achieved by genetic approaches or small molecules, it may now be possible to reach the goal of enhancing the concentration, conformation, quaternary structure, and/or location of a protein by readapting the innate biology of the cell to ameliorate the most challenging diseases of our era. Finally, we would like to thank our colleagues whose inspiration and generosity made this book a pleasure to plan and develop. The editors thank Richard Sever and Barbara Acosta at Cold Spring Harbor Laboratory Press for their encouragement, support, and patience in seeing this project to the end.

RICHARD I. MORIMOTO DENNIS J. SELKOE JEFFERY W. K ELLY

Index

A protein folding, 71–72 AAAþ chaperones, 21–22 protein trafficking, 74 AAAþ proteases, 20–21, 167–168 proteostasis collapse, 67–79 ABCA4 mutations, 300–301 proteostasis importance in, 69–70 Aggregation role in Huntington’s disease, 213–214 adaptation of proteostasis network to ameliorate translation rate and, 70–71 disease, 316–329 ubiquitin-proteasomal system (UPS), 75–76 adapting proteostasis to ameliorate diseases, unfolded protein response (UPR), 73 307–333 ALIS, 38 aggregate clearance by asymmetric damage a1-antichymotrypsin mutation, 190 inheritance, 22–23 a1-antitrypsin deficiency, 181–192 in a1-antitrypsin deficiency, 182–184 activating proteolytic degradation by lysosome, 329 Alzheimer’s disease Ab aggregates, 76–78 carcinogenesis, 181–192 biological regulation of, 7–9 cellular response pathways and ATZ accumulation chaperones and, 35–36, 114–115 in ER, 188–189 chemical regulation of, 9–10 determinants of tissue-specific damage, 184–185 chemical strategies to ameliorate disease, 329–333 genetic and environmental modifiers, 185 as concentration-dependent process, 105 hepatic fibrosis, 181–192 disaggregation, small heat shock proteins and, 22 mitochondrial dysfunction in liver disease, 184 disease and, 2–4 other serinopathies compared, 189–192 energy landscape, 104, 312 overview, 181–182 generic view of proteasomal and autophagic pathways as modifiers biological regulation of aggregation, 7–9 of tissue damage, 185–188 chemical regulation of aggregation, 9–10 protein aggregation role in tissue damage, 182–184 kinetics of aggregation, 4–6 therapeutic strategies, 189 protein solubility, key role of, 4, 5 variations in clinical disease among thermodynamics of aggregation, 6–7 homozygotes, 185 Huntington’s disease, inclusion bodies in, 215–224 a-synuclein Parkinson’s disease described, 237 a-synuclein, 238 misfolding and aggregation, 238 parkin, 240–241 posttranslational modifications, 238–239 reversing by AAAþ chaperones, 21–22 protein sequence, schematic of, 242 Aging variants, 237–238 autophagy, 74–75 ALS. See Amyotrophic lateral sclerosis (ALS) diseases of misfolding, 76 Alzheimer’s disease, 195–206 evolutionary tradeoffs, 78 Ab aggregates, detoxification of, 76–78 heat shock response, 72–73 Ab generation by regulated proteolysis of precursor hypoxia response, 73 protein, 197–199 mitochondrial quality control, 173–174 genetics of, 199 neurodegenerative disease, 76–78 genotype-to-phenotype relationships in familial AD, pathways that influence, 67–69 199–201 dietary restriction, 67, 68, 71 model in C. elegans,76–78 electron transport chain (ETC), 68 mouse models, genetically engineered, 78, 201–203 insulin-IGF-1-like signaling pathway (IIS), overview, 195–196 67–69, 71 protein chemical nature of diagnostic brain lesions, proteasomal degradation, 75–76 196–197 protein degradation, 74 retinal involvement, 303

Alzheimer’s disease (Continued) mitochondrial permeability transition, 155 synaptic form and function perturbation by signaling at mitochondrial-associated membranes prefibrillar forms of Ab, 203–204 (MAM), 152–154 therapeutic opportunities from mechanistic Calnexin, 123, 154 study of Ab, 204–206 Calreticulin, 123, 154 Amyloid b-proteins (Ab), 196–206 Carbamazepine, 189, 190 Amyloid plaques/filaments Carcinogenesis, in a1-antitrypsin deficiency, 181–192 in Alzheimer’s disease, 195–206 CFTR (cystic fibrosis transmembrane conductance prion protein (PrP), 260, 266 regulator), 281–282, 284–293, Amyotrophic lateral sclerosis (ALS), 246–253 325–326 fused in sarcoma/translocated in liposarcoma Chaperone-mediated autophagy (CMA), 50–52 (FUS/TLS), 250–253 Chaperones overview, 236–237 AAAþ,21–22 RNA quality control and, 249 aging and protein folding, 71–72, 114–115 SOD1 altering chaperone-cochaperone interactions to in familial ALS, 246–248 enhance degradation, 319–320 in sporadic ALS, 248–249 autophagy and, 50–52 TDP-43, 249–250 balancing between folding, degradation, and Antithrombin mutations, 191 aggregation, 35–36 Apoptosis, ER stress-induced, 151–152 chaperonins, 109–111 APP (b-amyloid precursor protein), 197–200, classes of, 35–36, 106 202–204 CLIPS (chaperones linked to protein synthesis), 35 ATF6, 148–150 co-chaperones, 123–124, 319–320 ATP-dependent proteolysis in mitochondrial matrix, cytosolic machinery, 106 165–167 DnaK system, 15 Autophagy GroE system, 15–16, 109–111 aging and, 74–75 heat shock response and, 18 in a1-antitrypsin deficiency, 186–187 HSP70 family, 107–109 chaperone-mediated (CMA), 50–52 Hsp90 system, 110, 111–112 chemical modulation of clearance, 55 in Huntington’s disease, 217–219 clearance and, 49–55 at mitochondrial-associated membranes (MAMs), described, 49–50 154–155 macroautophagy, 51–52, 74–75 mitochondrial quality control and, 162, 163–165 microautophagy, 52 networks, 87–88 mitophagy, 172 overview, 105–106 pathophysiology of quality control through, 53–55 pharmacologic, 329–330 pathway characteristics, 50–52 in prokaryotes, 15–16 pathway of misfolded protein degradation, 37 quality control and, 48 physiological functions of, 52–53 ribosome-associated, 106, 107, 314–315 specialization, 95–96 stress responses, 72, 112–114 B Chaperones linked to protein synthesis (CLIPS), 35 Bacteria. See Prokaryotes Chaperonins, 109–111 Bestrophin 1, 301 Chronic obstructive pulmonary disease (COPD), in b-amyloid precursor protein (APP), 197–200, 202–204 a1-antitrypsin deficiency, 184–185 Bip, 123–124, 148–149 Chronic wasting disease (CWD), 263–264 Bovine spongiform encephalopathy (BSE), 263–264 CJD. See Creutzfeldt–Jakob disease Bunina bodies, in amyotrophic lateral sclerosis (ALS), Clearance mechanisms 236 autophagy, 49–55 chaperone-mediated (CMA), 52 chemical modulation, 55 C described, 49–50 C1 inhibitor mutations, 191 macroautophagy, 51–52 CAG expansion, in Huntington’s disease, 76, 212–215 microautophagy, 52 Calcium pathophysiology of quality control through, balance, endoplasmic reticulum, 135–136 53–55

pathway characteristics, 50–52 altering chaperone-cochaperone interactions to physiological functions of, 52–53 enhance, 319–320 integration of, 47–62 chaperones and, 35–36 intracellular, 48–49 endoplasmic reticulum and (see ER-associated ubiquitin/proteasome system (UPS), 55–61 degradation) 26S proteasome, 59 pathways of misfolded protein, 36–37 chemical modulation, 61 retrotranslocation and, 132 components, 56 Deubiquitinating enzymes (DUBs), 59 decoding ubiquitination at the proteasome, Diabetes, 78, 326–327 58–59 Dietary restriction pathway, 67, 68, 71 described, 55–56 Disaggregation, small heat shock proteins and, 22 pathophysiology of quality control, 60 Disulfide bond formation, 124–125 ubiquitination language, 57–58 DJ-1 gene, 246 ubiquitin conjugation, 56–57 DnaK system, 15, 18–20 CLIPS (chaperones linked to protein synthesis), 35 Dsb proteins, 25–26 ClpP protease, 166–167 DUBs (deubiquitinating enzymes), 59 Co-chaperones, 123–124, 319–320 COPD (chronic obstructive pulmonary disease), in a1-antitrypsin deficiency, 184–185 E Creutzfeldt–Jakob disease (CJD), 261, 263 E3 ligases, 37, 57, 126 familial (fCJD), 261, 263 EDEM proteins, 131–132, 133 iatrogenic (iCJD), 263 Electron transport chain (ETC) pathway, 68 sporadic (sCJD), 261 ELOVL4 mutations, 300 variant (vCJD), 263 Endoplasmic reticulum CWD (chronic wasting disease), 263–264 a1-antitrypsin mutant protein accumulation in, Cystatin C, 236 188–189 Cystic fibrosis, 281–293 calcium and mitochondrial permeability transition, pathological triad, 281, 282 155 proteostasis network, 324–326 cell survival and death, role in, 147–156 CFTR biology and, 285–287 homeostasis, 133–136 emergent properties as guide for rescue of calcium balance, 135–136 misfolding disease, 293 redox, 134–135 as framework for disease management, mitochondria interactions, 152–153 282–285 posttranslational modifications, 123–125 management of vCFTR functions by, 290 disulfide bond formation, 124–125 model systems, 289–291 glycosylation, 123 therapeutics and, 287–291 protein folding and quality control in, 121–137 as systems disease, 281–282 protein folding by chaperones and co-chaperones, therapeutics 123–124 new targets affecting restoration of tissue specialized compartments within, 136 function, 292–293 therapeutics and, 136–137 proteostasis network and, 287–291 translation of ER-targeted proteins, 121, 123 trafficking, 284–285 unfolded protein response (UPR), 148–151 Cystic Fibrosis Foundation Therapeutics modulator up-regulation of proteostasis network by calcium library, 287 increase, 328–329 Cystic fibrosis transmembrane conductance regulator Endoplasmic reticulum secretory compartment, (CFTR), 281–282, 284–293, 325–326 proteostasis challenges of, Cytosolic stress, 112 321–322 Energy landscape, of protein folding and aggregation, 104, 310, 312 D Environmental stress response, 35 DAF-16, 77 ER-associated degradation (ERAD), 125–133 DALIS, 38 motif names, table of, 130–131 DegP, 24–25 pathway of misfolded protein degradation, 37 Degradation pathways, 133 aging and, 74, 75–76 proteins, table of, 128–129

ER-associated degradation (Continued) aging and, 72–73 recognition and targeting, 125, 127, 131–132 cytosolic/nuclear compartment, 313–316 retrotranslocation and degradation, 132–133 HSF axis, 112–114 ERdj proteins, 123–124 Hsp90 inhibitors to induce, 320–321 ER stress, 147–156 proteasome inhibitors and, 327–328 death response, 151–152 Heparin cofactor II mutations, 190 unfolded protein response (UPR), 73 Hepatic fibrosis, in a1-antitrypsin deficiency, Exotic ungulate encephalopathy, 263 181–192 Eye HIF1, 73 protein misfolding and retinal degeneration, Homeostasis. See also Proteostasis 297–304 endoplasmic reticulum, 133–136 structure and function, 297–298 protein integrating strategies in prokaryotes, 13–26 overview of, 3 F protein solubility, key role of, 4, 5 Fabry disease, 329 HSF-1. See Heat shock factor 1 Familial encephalopathy with neuroserpin inclusion Hsp40 family, 123–124 bodies (FENIB), 191 Hsp60, 165 Fatal familial insomnia (FFI), 261, 263 HSP70 family, 107–109 Fibulin-3, 301 Hsp78, 165 FoldEx, 285 Hsp90 system, 110, 111–112, 320–321 Folding. See Protein folding HtrA2 protease, 168 FOXO signaling, 316–318 Huntington, George, 211 FtsH protease, 21 Huntington’s disease, 211–227 Fungal prions, 260, 271 aging, role of, 213–214 Fused in sarcoma/translocated in liposarcoma correlations to protein accumulation, 215 (FUS/TLS), 250–253 evidence of a proteopathy, 214–215 genetic determinants G of symptom onset and disease progression, Gain-of-function disorders 212–213 a1-antitrypsin deficiency, 181–192, 329 of symptom profile and neuropathy, 213 leucine-rich repeat kinase-2 (LRRK2) mutations, genotype–phenotype correlations, clinical overview 243–244 of, 212–214 serinopathies, 189–192 history, 211 Gaucher’s disease, 329–330 HTT aggregation, 215 Gene therapy, for retinal degenerations, 304 inclusion body Genetic variation, natural, 96–97 formation, 215 Gerstmann–Staüssler–Scheinker (GSS) syndrome, 261 as mismatch of protein production and GroE system, 15–16, 18–19, 109–111 clearance, 215–217 Guanabenz, 327 as regulated mechanism to cope with misfolded proteins, 221–224 significance to neurodegeneration, 219–221 H integrated view of misfolding and Heat shock factor 1 (HSF1), 72, 76–77, 88–90, 94, neurodegeneration in, 224–227 96, 113–114, 313, 314 misfolding leading to neurodegeneration, Heat shock proteins 225–227 disaggregation and, 22 network for protein homeostasis, 224–225 Hsp40 family, 123–124 protein folding and molecular chaperones, 217–219 Hsp60, 165 proteostasis and, 214–224 HSP70 family, 107–109 Huttingtin (Htt) protein. See Huntington’s disease Hsp78, 165 Hypoxia response, aging and, 73 Hsp90 system, 110, 111–112, 320–321 transcriptional regulation of, 113, 114 Heat shock response I activating to ameliorate degeneration of postmitotic Inclusion bodies in Huntington’s disease, 215–224 tissue, 316, 318 Insulin growth factor-1 signaling, 316–319

Insulin-IGF-1-like signaling pathway (IIS) cellular strategies in protein quality control, pathway, 67–69, 71 33–42 IPOD, 38–39 chemical strategies to ameliorate disease, IRE1, 148–150 329–333 cystic fibrosis transmembrane conductance regulator (CFTR), 281–282, 284–293 J generic view of, 1–10 JUNQ, 38–39 aggregation and disease, 2–4 biological regulation of aggregation, 7–9 K chemical regulation of aggregation, 9–10 kinetics of aggregation, 4–6 Kinetics of protein aggregation, 4–6 metastability, 7 Kinetic stabilizers, 330–333 protein folding and misfolding, 2 Kuru, 263 protein solubility in homeostasis, key role of, 4 thermodynamics of aggregation, 6–7 L Huntington’s disease, 221–227 Leucine-rich repeat kinase-2 (LRRK2) mutations, Parkinson’s disease, 303 243–244 a-synuclein, 238 Levinthal paradox, 104 parkin, 240–241 Lewy bodies, Parkinson’s disease, 236–239, 241, 246 in prokaryotes, 13–14 Life cycle, protein, 70 retinal degeneration and, 297–304 Lon protease, 20–21, 165–166 serpins, 183 Lou Gehrig’s disease. See Amyotrophic lateral sclerosis SOD1 (superoxide dismutase-1), 246–248 (ALS) stress of, 85–98 LRRK2 (leucine-rich repeat kinase-2) mutations, unified view of, 10 243–244 Mitochondria Lung injury, in a1-antitrypsin deficiency, 184–185 a1-antitrypsin deficiency and liver disease, 184 Lysosomal enzymes, pharmacologic chaperones to endoplasmic reticulum interactions, 152–153 prevent misfolding and degradation of, 329– evolution of, 161 330 function of, 161–162 Lysosomal storage diseases, 322–324, 329 fusion, proteolytic control of, 170–172 Lysosomes, 49–55, 329. See also Autophagy mitophagy, 172 outer membrane proteins, turnover of, 168–170 permeability transition, 155 M proteases, 165–168 Macroautophagy, 51–52, 74–75 AAA, 167–168 Mad cow disease, 263 ClpP, 166–167 Malattia Leventinese, 301 HtrA2, 168 MAM (mitochondrial-associated membranes), Lon, 165–166 152–155 Oma1, 168 Manganese superoxide dismutase, 165 quality control, 161–174 Megsin, 191–192 reticular networks, 162 Metabolic syndrome, 78, 326 Mitochondrial-associated membranes (MAMs), Metastability of human proteome, 7 152–155 Mice, transgenic Mitochondrial quality control, 161–174 Alzheimer’s disease models, 201–203 in aging and disease, 173–174 prions, 264–265 chaperones, 162, 163–165 Microautophagy, 52 proteases and, 165–168 Misfolding of proteins ATP-dependent proteolysis in mitochondrial AAAþ protease removal, 20–21 matrix, 165–167 adaptation of proteostasis network to ameliorate proteolytic systems, 166 disease, 316–329 QC across the inner membrane, 167–168 adapting proteostasis to ameliorate diseases, QC in intermembrane space, 168 307–333 proteolytic control of fusion and mitophagy, in Alzheimer disease, 303 170–172 causes and consequences of, 34–35 surveillance mechanisms, 161–174

Mitochondrial quality control (Continued) DJ-1 gene, 246 ubiquitin/proteasome system (UPS), 162, leucine-rich repeat kinase-2 (LRRK2) mutations, 168–170 243–244 unfolded protein response (UPR), mitophagy, 172 mitochondria-specific, 172–173 overview, 236–237 Mitophagy, 172 parkin, 172 Molecular chaperones. See Chaperones described, 239–240 Movement disorders, 235–253 postmortem evaluation of stability, 242–243 amyotrophic lateral sclerosis (ALS), 246–253 posttranslational modifications, 241–242 overview, 235–237 proteostasis, 243 Parkinson’s disease, 237–246 stability, impact of disease-linked truncations MtHsp70, 164–165 and mutations on, 240 stress-induced misfolding and aggregation, 240–241 N pathway for, 245 Neurodegenerative disease PINK1 gene, 244 aging, 76–78 retinal involvement, 303 Alzheimer’s disease, 195–206 UCH-L1, 244–246 amyotrophic lateral sclerosis (ALS), 246–253 PDI family proteins, 124 Huntington’s disease, 211–227 Periplasmic quality control system, 24–26 Parkinson’s disease, 237–246 PERK, 148–151, 326–327 Neurofibrillary tangles, in Alzheimer’s disease, 195, Pharmacologic chaperones, 329–330 196–197 in cystic fibrosis, 287–288 Neurologic disorders of movement, 235–253 for photoreceptors, 303 amyotrophic lateral sclerosis (ALS), 246–253 Phosphodiesterase 6 (PDE6) mutations, 300 overview, 235–237 Photoreceptors, unfolded protein response (UPR) in, Parkinson’s disease, 237–246 299–301 Neuroserpin gene mutations, 191 Pick’s disease, 272 Nucleation-elongation-fragmentation model of fibril PINK1, 172, 244 formation, 5, 6 PME (progressive myoclonus epilepsy), 191 Polyglutamine (polyQ) expansion, in Huntington’s disease, 76, 212–221, 224–227 O Polymorphisms, 96–97 Oligosaccharyltransferase, 123 Postmitotic tissue degeneration, 316, 318, 330–333 Oma1 protease, 168 Posttranslational modifications, 123–125 OPA1 (Optic atrophy 1), 169–172 disulfide bond formation, 124–125 Outer membrane proteins (OMPs), 24 glycosylation, 123 Oxidative stress, 19–20 Parkinson’s disease a-synuclein, 238–239 parkin, 241–242 P Presenillin 1 and presenillin 2, 199, 201, 202 Parkin, 172 Prion-like diseases, 272–273 described, 239–240 Prions, 259–273 postmortem evaluation of stability, 242–243 amyloid, 260, 266 posttranslational modifications, 241–242 bioluminescence imaging, 266, 267 proteostasis, 243 characteristics of mammalian, 272 stability, impact of disease-linked truncations de novo generation of, 268–271 and mutations on, 240 diseases stress-induced misfolding and aggregation, 240–241 in animals, 263–264 Parkinson’s disease, 237–246 in humans, 261, 263 a-synuclein table of, 262 described, 237 therapeutics for, 273 misfolding and aggregation, 238 formation, cell biology of, 268 posttranslational modifications, 238–239 fungal, 260, 271 protein sequence, schematic of, 242 prion-like diseases, 272–273 variants, 237–238 protein isoforms, 259–260

PrP genes, 260–261, 262 chaperone systems, 15–16 replication, 265–266 ribosome-bound trigger factor and, 14–15 strains, 271–272 Protein quality control structural features of PrP, 268, 269, 270 causes and consequences of misfolding, 34–35 transgenic mice, 264–265 cellular strategies in, 33–42 Progressive myoclonus epilepsy (PME), 191 chaperones and, 35–36 Prokaryotes compartments in eukaryotic cells, 39 AAAþ chaperones, reversing aggregation model for misfolded protein toxicity in by, 21–22 amyloidogenic disease, 41 AAAþ proteases, removal of misfolded proteins pathways of misfolded protein degradation, 36–37 by, 20–21 protein sequestration, advantages of, 40 adjusting quality control networks to environmental role in cellular integrity, 33–34 stress, 16–18 spatial organization of pathways, 37–40 aggregate clearance by asymmetric damage Protein sequestration, advantages of, 40 inheritance, 22–23 Protein trafficking, aging and, 74 asymmetric damage inheritance, 22–23 Proteome challenges to quality control systems during stress, maintaining functional, 87–91 18–20 chaperone networks, 87–88, 89 disaggregation, heat shock proteins and, 22 stress response, role of, 88–90 misfolding and quality control systems, 13–14 variation, natural genetic, 96–97 polar aggregate deposition in E. coli,23 Proteostasis protein folding activating protein degradation to reestablish chaperone systems, 15–16 cytolsolic, 319 ribosome-bound trigger factor and, 14–15 aging as event of collapse in, 67–79 stress responses, regulation of, 16–18 challenges of the endoplasmic reticulum secretory Proteases compartment, 321–322 AAAþ, 20–21, 167–168 in extracytoplasmic compartments, 24–26 ClpP, 166–167 Huntington’s disease and, 214–224 HtrA2, 168 organismal Lon, 20–21, 165–166 chaperone specialization, 95–96 mitochondria, 165–168 nonautonomous regulation, 93–94 Oma1, 168 pathways, 90 Proteasomal degradation quality control of mitochondrial, 161–174 aging, 75–76 regulators in cystic fibrosis, 288 pathway in a1-antitrypsin deficiency, stress-response signaling to maintain in the 185–186 endoplasmic reticulum, 322 Proteasome Proteostasis network activating degradation to reestablish cytolsolic adaptation to ameliorate disease, 316–329 proteostasis, 319 components of, 282–283 decoding ubiquitination at, 58–59 in cystic fibrosis, 281–293, 324–326 inhibitors and heat shock response, 327–328 CFTR biology and, 285–287 26S, 59 emergent properties as guide for rescue of Protein folding. See also Misfolding of proteins misfolding disease, 293 aging and, 71–72 framework for disease management, 282–285 in cytoplasm, 103–115 management of vCFTR functions by, 290 chaperones, 106–114 model systems, 289–291 energy landscape, 104 therapeutics and, 287–291 heat shock response and, 103–115 diabetes/metabolic syndrome alleviation and, 326 overview, 103–115 matching misfolded protein load, 92 in endoplasmic reticulum, 121–137 up-regulation of by ER calcium increase, 328–329 energy landscape, 104, 310, 312 Levinthal paradox, 104 molecular chaperones, 105–114 (see also Q Chaperones) Quality control overview, 309–313 autophagy, 53–55 in prokaryotes cellular strategies in protein QC, 33–42

Quality control (Continued) advantages of protein, 40 in endoplasmic reticulum, 121–137 of aggregates at polar sites in E. coli,23 of mitochondrial proteostasis, 161–174 Serpinopathies overview, 85–87 a1-antichymotrypsin mutation, 190 prokaryotes a1-antitrypsin deﬁciency, 181–192 adjusting networks to environmental stress, antithrombin mutations, 191 16–18 C1 inhibitor mutations, 191 challenges during stress conditions, 18–20 heparin cofactor II mutations, 190 in periplasm, 24–26 neuroserpin gene mutations, 191 protein misfolding and, 13–14 Serpins RNA and ALS, 249 folding and misfolding, 183 Ubiquitin/proteasome system (UPS), 60, 162, megsin, 191–192 168–170 SOD1 (superoxide dismutase-1), in ALS, 41, 246–249 familial, 246–248 sporadic, 248–249 R Solubility, role in homeostasis, 4, 5 Reactive oxygen species (ROS), 165 Stargardt’s disease, 302 Redox homeostasis, endoplasmic reticulum, 134–135 Stress, cytosolic, 112 Retina, structure and function of, 297–298 Stress-induced misfolding and aggregation of parkin, Retinal degeneration, protein misfolding and, 297–304 240–241 diseases Stress-induced mitochondrial hyperfusion (SIMH), 163 Alzheimer disease, 303 Stress of misfolding of proteins, 85–98 Parkinson’s disease, 303 Stress response. See also Unfolded protein response retinitis pigmentosa, 302 (UPR) role of misfolded proteins, 301–302 HSF axis, 112–114 Stargardt’s disease, 302 maintaining functional proteome, role in, 88–91 systemic diseases, 303 Stress responses therapeutic strategies for correction of misfolding, in bacteria 303–304 challenges to quality control systems during unfolded protein response (UPR), 298–301 stress, 18–20 ABCA4 mutations, 300–301 regulation of, 16–18 ELOVL4 mutations, 300 chaperones and, 72 mild response as protective, 301 phosphodiesterase 6 (PDE6) mutations, 300 in photoreceptors, 299–301 T in retinal pigment epithelium (RPE), 301 Tau, 196–197, 199, 205 retinoschisin, 301 TDP-43, 249–250 rhodopsin mutations, 299–300 Temperature-responsive RNAs, 17–18 Retinal pigment epithelium (RPE) Thermodynamics of protein aggregation, 6–7 structure and function, 298 TOR, 71 unfolded protein response (UPR), 301 Transcriptional regulation of heat shock proteins, 113, Retinitis pigmentosa, 302 114 Retinoschisin, 301 Translational attenuation, 326–327 Retrotranslocation, 132 Translation of ER-targeted proteins, 121, 123 Rhodopsin mutations, 299–300 Translation rates, 70–71 Ribosome-associated chaperones, 106, 107, 314–315 Transmissible mink encephalopathy (TME), 263 RNA quality control, amyotrophic lateral sclerosis (ALS) Transthyretin amyloidogenesis, 330–333 and, 249 TriC/CCT, 111, 315 RNA thermometers, 17–18 Trigger factor, 14–15, 106, 107 ROS (reactive oxygen species), 165 26S proteasome, 59 ROSE element, 18 U S Ubiquitination Scrapie, 264 conjugation, 56–57 Sequestration decoding at the proteasome, 58–59

deubiquitinating enzymes (DUBs), 59 prolonging, 326–327 language, 57–58 in retinal degeneration, 298–301 Ubiquitin/proteasome system (UPS), 55–61 ABCA4 mutations, 300–301 aging and, 75–76 ELOVL4 mutations, 300 chemical modulation, 61 mild response as protective, 301 clearance mechanisms, 55–61 phosphodiesterase 6 (PDE6) mutations, 300 components, 56 in photoreceptors, 299–301 decoding ubiquitination at the proteasome, 58–59 in retinal pigment epithelium (RPE), 301 described, 55–56 retinoschisin, 301 mitochondrial quality control and, 162, 168–170 rhodopsin mutations, 299–300 pathophysiology of quality control, 60 Unfolded protein titration model, 18 pathway of misfolded protein degradation, 36 UPR. See Unfolded protein response (UPR) 26S proteasome, 59 UPS. See Ubiquitin/proteasome system (UPS) ubiquitination language, 57–58 ubiquitin conjugation, 56–57 UCH-L1 gene, 244–246 V Unfolded protein response (UPR) Variation, natural genetic, 96–97 absence in a1-antitrypsin deﬁciency, 188–189 Vertex 809/Vertex 770, 288–289, 293 aging and, 73 Voltage-dependent anion channel (VDAC), 154, 155 branches of, 298–299 described, 298–299 endoplasmic reticulum and, 73, 148–151 Y mitochondria-speciﬁc, 162, 172–173 Yeast prions, 260, 271

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