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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 medicine, proteopathy (Proteo- [pref. protein]; -pathy [suff. disease]; proteopathies pl.; proteopathic adj.) refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body.[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 Creutzfeldt–Jakob disease, Alzheimer's disease, Parkinson's disease, prion disease, 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, Rudolf Virchow coined the term amyloid ("starch-like") to describe a substance in cerebral corpora amylacea that exhibited a chemical reaction resembling that of cellulose. In 1859, Friedreich and Kekulé demonstrated that, rather than consisting of cellulose, "amyloid" actually is rich in protein.[9] Subsequent research has shown that many different proteins can form amyloid, and that all amyloids have in common birefringence in cross-polarized light after staining with the dye Congo Red, as well as a fibrillar ultrastructure when viewed with an electron microscope.[9] However, some proteinaceous lesions lack birefringence and contain few or no classical amyloid fibrils, such as the diffuse deposits of Aβ protein in the brains of Alzheimer patients.[10] Furthermore, evidence has emerged that small, non-fibrillar protein aggregates known as oligomers are toxic to the cells of an affected organ, and that amyloidogenic proteins in their fibrillar form may be relatively benign.[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[edit]

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 host by the introduction of diseased tissue extract from an afflicted donor. The best known form of such inducible proteopathy is prion disease, which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation.[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[edit]

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[edit]


  1. ^ a b c Walker LC, LeVine III H (2000). "The cerebral proteopathies". Neurobiol Aging 21 (4): 559–561. doi:10.1016/S0197-4580(00)00160-3. PMID 10924770. 
  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. doi:10.1385/MN:21:1-2:083. PMID 11327151. 
  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. doi:10.1016/j.cbpa.2008.02.011. PMID 18295611. 
  4. ^ Chiti F, Dobson CM (2006). "Protein misfolding, functional amyloid, and human disease". Ann Rev Biochem 75 (1): 333–366. doi:10.1146/annurev.biochem.75.101304.123901. PMID 16756495. 
  5. ^ Friedrich O (2006). "Critical illness myopathy: what is happening?". Current Opinion in Clinical Nutrition and Metabolic Care 9 (4): 403–409. doi:10.1097/01.mco.0000232900.59168.a0. PMID 16778569. 
  6. ^ Spinner NB (2000). "CADASIL: Notch signaling defect or protein accumulation problem?". J Clin Invest 105 (5): 561–562. doi:10.1172/JCI9511. PMC 292459. PMID 10712425. 
  7. ^ a b c d e Carrell RW, Lomas DA (1997). "Conformational disease". Lancet 350 (9071): 134–138. doi:10.1016/S0140-6736(97)02073-4. PMID 9228977. 
  8. ^ Westermark P, et al. (2007). "A primer of amyloid nomenclature". Amyloid 14 (1): 179–183. doi:10.1080/13506120701460923. PMID 16076605. 
  9. ^ a b Sipe JD, Cohen AS (2000). "Review: History of the amyloid fibril". J Struct Biol 130 (2–3): 88–98. doi:10.1006/jsbi.2000.4221. PMID 10940217. 
  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. doi:10.1097/00005072-199807000-00004. PMID 9690671. 
  11. ^ Glabe CG (2006). "Common mechanisms of amyloid oligomer pathogenesis in degenerative disease". Neurobiol Aging 27 (4): 570–575. doi:10.1016/j.neurobiolaging.2005.04.017. PMID 16481071. 
  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. doi:10.3233/JAD-2011-110182. PMID 21460436. 
  13. ^ Ito D, Suzuki N (2011). "Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS". Neurology 77 (17): 1636–43. doi:10.1212/WNL.0b013e3182343365. PMC 3198978. PMID 21956718. 
  14. ^ a b c d Dobson CM (1999). "Protein misfolding, evolution and disease". TIBS 24 (9): 329–332. doi:10.1016/S0968-0004(99)01445-0. PMID 10470028. 
  15. ^ Selkoe DJ (2003). "Folding proteins in fatal ways". Nature 426 (6968): 900–904. doi:10.1038/nature02264. PMID 14685251. 
  16. ^ Collinge J, Clarke AR (2007). "A general model of prion strains and their pathogenicity". Science 318 (5852): 930–936. doi:10.1126/science.1138718. PMID 17991853. 
  17. ^ Colby DW, Prusiner SB (2011). "De novo generation of prion strains". Nature Reviews Microbiology. Epub ahead of print Sept 26 (11): 771–7. doi:10.1038/nrmicro2650. PMID 21947062. 
  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. doi:10.1056/NEJMp1007051. PMID 20879875. 
  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. PMC 2656298. PMID 19300591. 
  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. doi:10.1042/BST0330578. PMID 16042548. 
  21. ^ a b Walker LC, LeVine H, Mattson MP, Jucker M (2006). "Inducible proteopathies". TINS 29 (8): 438–443. doi:10.1016/j.tins.2006.06.010. PMID 16806508. 
  22. ^ Prusiner SB (2001). "Shattuck lecture—Neurodegenerative diseases and prions". N Engl J Med 344 (20): 1516–1526. doi:10.1056/NEJM200105173442006. PMID 11357156. 
  23. ^ Zou WQ, Gambetti P (2005). "From microbes to prions: the final proof of the prion hypothesis". Cell 121 (2): 155–157. doi:10.1016/j.cell.2005.04.002. PMID 15851020. 
  24. ^ Meyer-Luehmann M, et al. (2006). "Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host". Science 313 (5794): 1781–1784. doi:10.1126/science.1131864. PMID 16990547. 
  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. doi:10.1038/ncb1901. PMC 2726961. PMID 19503072. 
  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. doi:10.1073/pnas.0903691106. PMC 2722313. PMID 19651612. 
  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. doi:10.1172/JCI43366. PMC 3026723. PMID 21245577. 
  28. ^ Kordower JH, et al. (2011). "Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat". Neurobiol Dis 43 (3): 552–557. doi:10.1016/j.nbd.2011.05.001. PMC 3430516. PMID 21600984. 
  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. doi:10.1038/nm1747. PMID 18391962. 
  30. ^ Chia R, et al. (2010). Feany MB, 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. doi:10.1371/journal.pone.0010627. PMC 2869360. PMID 20498711. 
  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. doi:10.1073/pnas.1017275108. PMC 3048161. PMID 21321227. 
  32. ^ Ren PH, et al. (2009). "Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates". Nat Cell Biol 11 (2): 219–225. doi:10.1038/ncb1830. PMC 2757079. PMID 19151706. 
  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. doi:10.1074/jbc.M111.231209. PMC 3099683. PMID 21454603. 
  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. doi:10.1073/pnas.0501814102. PMC 1087940. PMID 15829582. 
  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. doi:10.1016/S0014-5793(04)00295-9. PMID 15063745. 
  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. doi:10.2353/ajpath.2007.070403. PMC 2111123. PMID 18055549. 
  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. doi:10.1523/JNEUROSCI.5924-09.2010. PMC 2859074. PMID 20357103. 
  38. ^ Guo L, et al. (2007). "Targeting amyloid-β in glaucoma treatment". Proc Natl Acad Sci U S A 104 (33): 13444–13449. doi:10.1073/pnas.0703707104. PMC 1940230. PMID 17684098. 
  39. ^ Quinlan RA, Brenner M, Goldman JE, Messing A (2007). "GFAP and its role in Alexander Disease". Exp Cell Res 313 (10): 2077–2087. doi:10.1016/j.yexcr.2007.04.004. PMC 2702672. PMID 17498694. 
  40. ^ Ito D, Suzuki N (2009). "Seipinopathy: A novel endoplasmic reticulum stress-associated disease". Brain 32 (Pt 1): 8–15. doi:10.1093/brain/awn216. PMID 18790819. 
  41. ^ Surguchev A, Surguchov A (2010). "Conformational diseases: Looking into the eyes". Brain Res Bull 81 (1): 12–24. doi:10.1016/j.brainresbull.2009.09.015. PMID 19808079. 
  42. ^ Stuart MJ, Nagel RL (2004). "Sickle cell disease". Lancet 364 (9442): 1343–1360. doi:10.1016/S0140-6736(04)17192-4. PMID 15474138. 

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