World Library  
Flag as Inappropriate
Email this Article


Article Id: WHEBN0010348140
Reproduction Date:

Title: Proteopathy  
Author: World Heritage Encyclopedia
Language: English
Subject: Protein folding, Neurodegeneration, Folding@home, Protein aggregation, Tauopathy
Publisher: World Heritage Encyclopedia


Micrograph of a section of the cerebral cortex from a patient with Alzheimer's disease, immunostained with an antibody to (brown), a protein fragment that accumulates in senile plaques and cerebral amyloid angiopathy. 10X microscope objective.

In [1][2] Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a gain of toxic function) or they can lose their normal function.[3] The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases), include such diseases as Alzheimer's disease, Parkinson's disease, prion disease, type 2 diabetes, amyloidosis, and a wide range of other disorders (see List of Proteopathies).[2][4][5][6][7][8]

The concept of proteopathy can trace its origins to the mid-19th century, when, in 1854, [11][12]


In most, if not all proteopathies, a change in 3-dimensional folding (conformation) increases the tendency of a specific protein to bind to itself.[7] In this aggregated form, the protein is resistant to clearance and can interfere with the normal capacity of the affected organs. In some cases, misfolding of the protein results in a loss of its usual function. For example, cystic fibrosis is caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR) protein,[3] and in amyotrophic lateral sclerosis / frontotemporal lobar degeneration (FTLD), certain gene-regulating proteins inappropriately aggregate in the cytoplasm, and thus are unable to perform their normal tasks within the nucleus.[13] Because proteins share a common structural feature known as the polypeptide backbone, all proteins have the potential to misfold under some circumstances.[14] However, only a relatively small number of proteins are linked to proteopathic disorders, possibly due to structural idiosyncrasies of the vulnerable proteins. For example, proteins that are relatively unstable as monomers (that is, as single, unbound protein molecules) are more likely to misfold into an abnormal conformation.[7][14] In nearly all instances, the disease-causing molecular configuration involves an increase in beta-sheet secondary structure of the protein.[7][14][15] The abnormal proteins in some proteopathies have been shown to fold into multiple 3-dimensional shapes; these variant, proteinaceous structures are defined by their different pathogenic, biochemical, and conformational properties. They have been most thoroughly studied with regard to prion disease, and are referred to as protein strains.[16][17]

Immunostained α-synuclein (brown) in Lewy bodies (large clumps) and Lewy neurites (thread-like structures) in the cerebral cortex of a patient with Lewy body disease, a synucleinopathy. 40X microscope objective.

The likelihood that proteopathy will develop is increased by certain risk factors that promote the self-assembly of a protein. These include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance.[1][7][14] Advancing age is a strong risk factor,[1] as is traumatic brain injury.[18] In the aging brain, multiple proteopathies can overlap. For example, in addition to tauopathy and Aβ-amyloidosis (which coexist as key pathologic features of Alzheimer's disease), many Alzheimer patients have concomitant synucleinopathy (Lewy bodies) in the brain.[19]

Seeded induction of proteopathy

Some proteins can be induced to form abnormal assemblies by exposure to the same (or similar) protein that has folded into a disease-causing conformation, a process called 'seeding' or 'permissive templating'.[20][21] In this way, the disease state can be brought about in a susceptible [22][23] There is now evidence that other proteopathies can be induced by a similar mechanism, including amyloidosis, amyloid A (AA) amyloidosis, and apolipoprotein AII amyloidosis,[21][24] tauopathy,[25] synucleinopathy,[26][27][28][29] and the aggregation of superoxide dismutase-1 (SOD1),[30][31] polyglutamine,[32] and TAR DNA-binding protein-43 (TDP-43).[33]

In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. In some cases, the deposition of one type of protein can be experimentally induced by aggregated assemblies of other proteins that are rich in β-sheet structure, possibly because of structural complementarity of the protein molecules. For example, AA amyloidosis can be stimulated in mice by such diverse macromolecules as silk, the yeast amyloid Sup35, and curli from the bacterium Escherichia coli.[34] In addition, apolipoprotein AII amyloid can be induced in mice by a variety of β-sheet rich amyloid fibrils,[35] and cerebral tauopathy can be induced by brain extracts that are rich in aggregated Aβ.[36] There is also experimental evidence for cross-seeding between prion protein and Aβ.[37] In general, such heterologous seeding is less efficient than is seeding by a corrupted form of the same protein.

List of proteopathies

Proteopathy Major aggregating protein
Alzheimer's disease Amyloid β peptide (); Tau protein (see tauopathies)
Cerebral β-amyloid angiopathy Amyloid β peptide ()
Retinal ganglion cell degeneration in glaucoma[38] Amyloid β peptide ()
Prion diseases (multiple) Prion protein
Parkinson's disease and other synucleinopathies (multiple) α-Synuclein
Tauopathies (multiple) Microtubule-associated protein tau (Tau protein)
Frontotemporal lobar degeneration (FTLD) (Ubi+, Tau-) TDP-43
FTLDFUS Fused in sarcoma (FUS) protein
Amyotrophic lateral sclerosis (ALS) Superoxide dismutase, TDP-43, FUS
Huntington's disease and other triplet repeat disorders (multiple) Proteins with tandem glutamine expansions
Familial British dementia ABri
Familial Danish dementia ADan
Hereditary cerebral hemorrhage with amyloidosis (Icelandic) (HCHWA-I) Cystatin C
Alexander disease[39] Glial fibrillary acidic protein (GFAP)
Seipinopathies[40] Seipin
Familial amyloidotic neuropathy, Senile systemic amyloidosis Transthyretin
Serpinopathies (multiple) Serpins
AL (light chain) amyloidosis (primary systemic amyloidosis) Monoclonal immunoglobulin light chains
AH (heavy chain) amyloidosis Immunoglobulin heavy chains
AA (secondary) amyloidosis Amyloid A protein
Type II diabetes Islet amyloid polypeptide (IAPP; amylin)
Aortic medial amyloidosis Medin (lactadherin)
ApoAI amyloidosis Apolipoprotein AI
ApoAII amyloidosis Apolipoprotein AII
ApoAIV amyloidosis Apolipoprotein AIV
Familial amyloidosis of the Finnish type (FAF) Gelsolin
Lysozyme amyloidosis Lysozyme
Fibrinogen amyloidosis Fibrinogen
Dialysis amyloidosis Beta-2 microglobulin
Inclusion body myositis/myopathy Amyloid β peptide ()
Cataracts Crystallins
Retinitis pigmentosa with rhodopsin mutations[41] rhodopsin
Medullary thyroid carcinoma Calcitonin
Cardiac atrial amyloidosis Atrial natriuretic factor
Pituitary prolactinoma Prolactin
Hereditary lattice corneal dystrophy Keratoepithelin
Cutaneous lichen amyloidosis Keratins
Mallory bodies Keratin intermediate filament proteins
Corneal lactoferrin amyloidosis Lactoferrin
Pulmonary alveolar proteinosis Surfactant protein C (SP-C)
Odontogenic (Pindborg) tumor amyloid Odontogenic ameloblast-associated protein
Seminal vesicle amyloid Semenogelin I
Cystic Fibrosis cystic fibrosis transmembrane conductance regulator (CFTR) protein
Sickle cell disease[42] Hemoglobin
Critical illness myopathy (CIM) Hyperproteolytic state of myosin ubiquitination

See also


  1. ^ a b c Walker LC, LeVine III H (2000). "The cerebral proteopathies". Neurobiol Aging 21 (4): 559–561.  
  2. ^ a b Walker LC, LeVine III H (2000). "The cerebral proteopathies: Neurodegenerative disorders of protein conformation and assembly". Mol Neurobiol 21 (1–2): 83–95.  
  3. ^ a b Luheshi M, Crowther DC, Dobson CM (2008). "Protein misfolding and disease: from the test tube to the organism". Current Opinion in Chemical Biology 12 (1): 25–31.  
  4. ^ Chiti F, Dobson CM (2006). "Protein misfolding, functional amyloid, and human disease". Ann Rev Biochem 75 (1): 333–366.  
  5. ^ Friedrich O (2006). "Critical illness myopathy: what is happening?". Current Opinion in Clinical Nutrition and Metabolic Care 9 (4): 403–409.  
  6. ^ Spinner NB (2000). "CADASIL: Notch signaling defect or protein accumulation problem?". J Clin Invest 105 (5): 561–562.  
  7. ^ a b c d e Carrell RW, Lomas DA (1997). "Conformational disease". Lancet 350 (9071): 134–138.  
  8. ^ Westermark P et al. (2007). "A primer of amyloid nomenclature". Amyloid 14 (1): 179–183.  
  9. ^ a b Sipe JD, Cohen AS (2000). "Review: History of the amyloid fibril". J Struct Biol 130 (2–3): 88–98.  
  10. ^ Wisniewski HM, Sadowski M, Jakubowska-Sadowska K, Tarnawski M, Wegiel J (1998). "Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease". J Neuropath Exp Neurol 57 (7): 674–683.  
  11. ^ Glabe CG (2006). "Common mechanisms of amyloid oligomer pathogenesis in degenerative disease". Neurobiol Aging 27 (4): 570–575.  
  12. ^ Gadad BS, Britton GB, Rao KS (2011). "Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide". Journal of Alzheimer's disease : JAD. 24 Suppl 2: 223–232.  
  13. ^ Ito D, Suzuki N (2011). "Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS". Neurology. Epub ahead of print Sept 28 (17): 1636–43.  
  14. ^ a b c d Dobson CM (1999). "Protein misfolding, evolution and disease". TIBS 24 (9): 329–332.  
  15. ^ Selkoe DJ (2003). "Folding proteins in fatal ways". Nature 426 (6968): 900–904.  
  16. ^ Collinge J, Clarke AR (2007). "A general model of prion strains and their pathogenicity". Science 318 (5852): 930–936.  
  17. ^ Colby DW, Prusiner SB (2011). "De novo generation of prion strains". Nature Reviews Microbiology. Epub ahead of print Sept 26 (11): 771–7.  
  18. ^ DeKosky ST, Ikonomovic MD and Gandy S (2010). "Traumatic brain injury--football, warfare, and long-term effects". New England Journal of Medicine 363 (14): 1293–1296.  
  19. ^ Mrak RE, Griffin WS (2007). "Dementia with Lewy bodies: Definition, diagnosis, and pathogenic relationship to Alzheimer's disease". Neuropsychiatr Dis Treat 3 (5): 619–625.  
  20. ^ Hardy J (2005). "Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: 'permissive templating' as a general mechanism underlying neurodegeneration". Biochem Soc Trans 33 (Pt 4): 578–581.  
  21. ^ a b Walker LC, LeVine H, Mattson MP, Jucker M (2006). "Inducible proteopathies". TINS 29 (8): 438–443.  
  22. ^ Prusiner SB (2001). "Shattuck lecture—Neurodegenerative diseases and prions". N Engl J Med 344 (20): 1516–1526.  
  23. ^ Zou WQ, Gambetti P (2005). "From microbes to prions: the final proof of the prion hypothesis". Cell 121 (2): 155–157.  
  24. ^ Meyer-Luehmann M, et al. (2006). "Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host". Science 313 (5794): 1781–1784.  
  25. ^ Clavaguera F, Bolmont T, Crowther RA et al (2009). "Transmission and spreading of tauopathy in transgenic mouse brain". Nature Cell Biology 11 (7): 909–13.  
  26. ^ Desplats P et al. (2009). "Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein". Proc. Natl. Acad. Sci. USA 106 (31): 13010–13015.  
  27. ^ Hansen C et al. (2011). "α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells". J Clin Invest 121 (2): 715–725.  
  28. ^ Kordower JH et al. (2011). "Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat". Neurobiol Dis 43 (3): 552–557.  
  29. ^ Kordower JH et al. (2008). "Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease". Nat Med 14 (5): 504–506.  
  30. ^ Chia R et al. (2010). Feany, Mel B., ed. "Superoxide Dismutase 1 and tgSOD1G93A Mouse Spinal Cord Seed Fibrils, Suggesting a Propagative Cell Death Mechanism in Amyotrophic Lateral Sclerosis". PLoS ONE. 5:e10627 (5): e10627.  
  31. ^ Munch C, O’Brien J, Bertolotti A (2011). "Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells". Proc Natl Acad Sci U S A 108 (9): 3548–3553.  
  32. ^ Ren PH et al. (2009). "Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates". Nat Cell Biol 11 (2): 219–225.  
  33. ^ Furukawa Y et al. (2011). "A Seeding Reaction Recapitulates Intracellular Formation of Sarkosyl-insoluble Transactivation Response Element (TAR) DNA-binding Protein-43 Inclusions". J Biol Chem 286 (21): 18664–18672.  
  34. ^ Lundmark K, Westermark GT, Olsen A, Westermark P (2005). "Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism". Proc Natl Acad Sci U S A 102 (17): 6098–6102.  
  35. ^ Fu X, Korenaga T, Fu L, et al (2004). "Induction of AApoAII amyloidosis by various heterogeneous amyloid fibrils". FEBS Lett 563 (1–3): 179–184.  
  36. ^ Bolmont T, Clavaguera F, Meyer-Luehmann M, et al (2007). "Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP × Tau Transgenic Mice". Am J Pathol 171 (6): 2012–2020.  
  37. ^ Morales R et al. (2010). "Molecular Cross-talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases". J Neurosci 30 (13): 4528–4535.  
  38. ^ Guo L et al. (2007). "Targeting amyloid-β in glaucoma treatment". Proc Natl Acad Sci U S A 104 (33): 13444–13449.  
  39. ^ Quinlan RA, Brenner M, Goldman JE, Messing A (2007). "GFAP and its role in Alexander Disease". Exp Cell Res 313 (10): 2077–2087.  
  40. ^ Ito D, Suzuki N (2009). "Seipinopathy: A novel endoplasmic reticulum stress-associated disease". Brain 32 (Pt 1): 8–15.  
  41. ^ Surguchev A, Surguchov A (2010). "Conformational diseases: Looking into the eyes". Brain Res Bull 81 (1): 12–24.  
  42. ^ Stuart MJ, Nagel RL (2004). "Sickle cell disease". Lancet 364 (9442): 1343–1360.  

External links

  • Amyloidosis
  • Prion-Related Diseases
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from World Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.